TrkA receptor tyrosine kinase antagonists and uses thereof

ABSTRACT

The present disclosure relates to novel synthetic substituted heterocyclic compounds and pharmaceutical compositions containing the same, said compounds being capable of inhibiting or antagonizing TrkA receptor tyrosine kinases. In some aspects, the disclosure provides a compound having a structural formula (I): 
     
       
         
         
             
             
         
       
     
     The disclosure further concerns the use of such compounds in the treatment and/or prevention of certain types of cancers, pain, inflammation, restenosis, atherosclerosis, psoriasis, thrombosis, Alzheimer&#39;s, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination.

CROSS REFERENCE TO RELATED APPLICATIONS

The present Application claims the benefit of priority to U.S.Provisional Application No. 61/936,267, filed on Feb. 5, 2014, theentire contents of which are hereby incorporated by reference in theirentirety for all purposes.

1. FIELD OF THE DISCLOSURE

The present disclosure relates to synthetic substituted heterocycliccompounds and pharmaceutical compositions containing the same that arecapable of inhibiting or antagonizing protein kinase activities. Thedisclosure further concerns the use of such compounds in the treatmentand/or prevention of certain types of cancers, itching, atopicdermatitis, scabies, pityriasis, inflammation, restenosis,atherosclerosis, psoriasis, thrombosis, Alzheimer's, pain, a disease,disorder, injury, or malfunction relating to dysmyelination ordemyelination or the disease or disorder associated with abnormalactivities of protein kinases.

2. BACKGROUND OF THE DISCLOSURE

Trk family proteins are receptor tyrosine kinases composed of threefamily members, TrkA, TrkB and TrkC. They bind with high affinity to,and mediate the signal transduction induced by the Neurotrophin familyof ligands whose prototype members are Nerve Growth Factor (NGF),Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin 3-5 (NT 3-5).In addition, a co-receptor lacking enzymatic activity, p75, has beenidentified which binds all neurotrophines (NTs) with low affinity andregulates neurotrophin signaling. A critical role of the Trks and theirligands during the development of the central and peripheral nervoussystems have been established through gene disruption studies in mice.In particular, TrkA-NGF interaction was shown as a requirement for thesurvival of certain peripheral neuron populations involved in mediatingpain signaling. It has been shown that increased expression of TrkA alsocorrelates with an increased level of pain in the case of pancreaticcancer (Zhu, et al, Journal of clinical oncology, 17:2419-2428 (1999)).Increased expression of NGF and TrkA was also observed in humanosteoarthritis chondrocytes (Iannone et al, Rheumatology 41:1413-1418(2002)).

TrkA (Troponyosin-receptor kinase A) is a cell surface receptor kinasecontaining an extracellular, a transmembrane, and a cytoplasmic kinasedomain. The binding of a neurotrophin triggers oligomerization of thereceptors, phosphorylation of tyrosine residues in the kinase domain,and activation of intercellular signaling pathways, including Ras/MAPKcascade, PI3K/AKT, and IP3-dependent Ca2+ release. Tyrosine kinaseactivity is an absolute requirement for signal transduction through thisclass of receptor. NGF receptors have been also found on a variety ofcell types outside of the nervous system. For example, TrkA has beenalso found on human monocytes, T- and B-lymphocytes and mast cells.

There are several examples of either ant-TrkA antibodies or anti-NGFantibodies known in the art. For example, PCT Publication Nos. WO2006/131952, WO 2005/061540 and EP 1181318 disclose use of anti-TrkAantibodies as effective analgesics in in-vivo animal models ofinflammatory and neuropathic pain. PCT Application Nos. WO 01/78698, WO2004/058184 and WO 2005/019266 disclose the use of an NGF antagonist forpreventing or treating pain. PCT Application WO 2004/096122 describes amethod for the treatment or the prevention of pain withco-administration of an anti-NGF antibody and an opioid analgesic. PCTApplication WO 2006/137106 discloses a method for the treatment or theprevention of pain with co-administration of an anti-TrkA antibody andan opioid analgesic. In addition, profound or significantly attenuatedreduction of bone pain caused by prostate cancer metastasis has beenachieved by utilization of an anti-NGF antibody (Sevik, M A, et al, Pain115:128-141 (2005)). Loss-of-function mutations in TrkA (NTRK1) lead tocongenital insensitivity to pain with anhidrosis [Nat Genet 1996;13:485-8] and the anti-NGF antibody tanezumab has demonstrated clinicalefficacy in osteoarthritis pain and diabetic neuropathic pain [N Engl JMed 2010; 363:1521-31; Arthritis Rheum 2013; 65:1795-803]. Additionally,Trk inhibitors show excellent efficacy in preclinical models of pain[Mol Pain 2010; 6:87-100]. Array has recently demonstrated equivalentefficacy with allosteric TrkA-selective inhibitors in pain models, whichhave the potential to be safer than pan-Trk inhibitors as discussedlater [Array Website, 2012. Available:http://www.arraybiopharrna.conm/_documents/Pubbcation/PubAttachment587.pdf[Last accessed 22 Jan. 2014].

There is some evidence that inhibition of Trks may be beneficial in thetreatment of Alzheimer's disease. NGF and TrkA levels are elevated inairways of asthmatics (asthma) [J Asthma 2013; 50:712-17; Respirology(2009) 14, 60-68; and PLoS ONE 4(7): e6444.doi:10.1371/journal.pone.0006444] and may contribute to inflammation,hyperresponsiveness and remodeling. NGF and TrkA has also been shown toexacerbate ovalbumin-induced airway inflammation in rodents [Exp TherMed 2013; 6:1251-8]. CT327 is a topical TrkA inhibitor that has beenclinically evaluated by Creabilis for chronic pruritus in diseases suchas atopic dermatitis, psoriasis and itch[http://clinicaltrials.gov/show/NCT01808157]. Inhibition of TrkA mayhave utility in the treatment of Chagas disease. Trypanosoma cruzi, theagent of Chagas' disease, utilizes Trk to invade various cell types inthe human host [Infect Immun 2009; 77: 1368-75; Infect Immun 2011;79:4081-7].

Selective inhibition of TrkA kinase activity may also have utility inthe treatment of ear diseases [Laryngoscope 2011 October;121(10):2199-213], liver cirrhosis and hepatocellular carcinoma [World JGastroenterol 2007 Oct. 7; 13(37): 4986-4995], Pulmonary InflammatoryDiseases [Immunology and Microbiology>>“Inflammatory Diseases—A ModernPerspective”, book edited by Amit Nagal, ISBN 978-953-307-444-3,Published: Dec. 16, 2011, Chapter 5: Expression and Role of the TrkAReceptor in Pulmonary Inflammatory Diseases], fibrosis [J Cell CommunSignal. March 2010; 4(1): 15-23. Patent Application: PCT/GB2004/004795],Pterygium [Int. J. Exp. Path. (2009), 90, 615-620], lung diseases[Expert Rev Respir Med. 2010 June; 4(3): 395-411.], pulmonarysarcoidosis [Dagnell et al. Respiratory Research 2010, 11:156], bladderdysfunction [Neurourology and Urodynamics 30:1227-1241 (2011); BJUInternational 111, 372-380; J Urol. 2013 August; 190(2): 757-764;Neurourology and Urodynamics 33:39-45 (2014)], lower urinary tractdysfunction [International Journal of Urology (2013) 20, 13-20], Paget'sdisease [J Cutan Pathol 2010: 37: 1150-1154], diabetic nephropathy[Diabetes. September 2012, Vol. 61 Issue 9, p 2280-2288; RegulatoryPeptides 135 (2006) 30-38.], irritable bowel syndrome[Neurogastroenterol Motil (2013) 25, e740-e754], radiation protection[Radiother Oncol. 2012 June; 103(3): 380-387].

Furthermore, pain, which can be caused by the disease itself or bytreatments, is common in people with cancer, although not all peoplewith cancer will experience pain. Approximately 30% to 50% of peoplewith cancer experience pain while undergoing treatment, and 70% to 90%of people with advanced cancer experience pain [Lesage P. and Portenoy RK. Cancer Control; Journal of the Moffitt Cancer Center 1999;6(2):136-145]. Cancer pain is a complex, temporally changing symptomwhich is the end result of mixed mechanism pain. It involvesinflammatory, neuropathic, ischemic, and compression mechanisms atmultiple sites [Pathophysiology of cancer pain and opioid tolerance. In:The British Pain Society's Cancer Pain Management. The British PainSociety website. www.britishpainsociety.org. Published January 2010.Accessed Jan. 29, 2013]. It is a subjective, heterogeneous experiencethat is modified by individual genetics, past history, mood,expectation, and culture. Cancer pain syndromes are categorized as acuteand chronic based on onset and duration. Acute pain syndromes have asudden, well-defined onset, an identifiable cause (e.g. surgery),subject to sympathetic output (fight or flight response), and areexpected to improve with management. Chronic pain on the other hand, hasa less distinct onset, has a prolonged and fluctuating course, and islargely driven by central sensitization and neuroplastic responses fromacute injury [Fornasari D. Pain mechanisms in patients with chronicpain. Clin Drug Investig 2012; 32(suppl 1):45-52; Latremoliere A, WoolfC J. Central sensitization: a generator of pain hypersensitivity bycentral neural plasticity. J Pain 2009; 10:895-926]. It is oftencharacterized by “pain flares” referred to as breakthrough pain[Portenoy R K, Dhingra L K. Assessment of cancer pain. In: Drews R E,ed. UpToDate. Waltham, Mass.: UpToDate; 2013].

The therapeutic implications of an effective Trk inhibitor may well gobeyond pain therapy. A TrkA polymorphism has been identified to beassociated with schizophrenia [J Psychiatr Res. 2009 October;43(15):1195-9]. The subversion of this receptor and its signalingpathway in certain malignancies has also been documented. The potentialutility of Trk inhibitors in oncology has been covered previously (forreviews, see, Expert Opin Ther Pat. 2014 July; 24(7):731-44; Nat RevCancer, 2004: 4:361-70; Clin Cancer Res, 2009; 15:5962-7). TrkA and/orTrk(B/C) have been implicated in the survival and metastasis of prostate[Expert Opin Investig Drugs, 2007; 16:303-9; Prostate, 2000:45:140-8],breast [Cytokine Growth Factor Rev, 2012; 23; 357-65], hepatocellularcarcinoma (liver cancer) and liver cirrhosis [World J Gastroenterol.2007 Oct. 7; 13(37):4986-95; Gastroenterology. 2002 June;122(7):1978-86; Biochem Biophys Res Commun. 2011 Mar. 4; 406(1):89-95;Digestive Diseases and Sciences, Vol. 55, No. 10, (October 2010), pp.2744-55, ISSN 0163-2116], intrahepatic cholangiocarcinoma [World JGastroenterol 2014 Apr. 14; 20(14): 4076-4084], liver fibrosis [ExpertRev Mol Med.; 11: e7. doi:10.1017/S1462399409000994], ovarian cancer[Gynecol Oncol. 2007 January; 104(1):168-75], pancreatic cancers [ClinCancer Res., 2005; 11:440-9], oral cancer [Dermatol Surg 2004;30:1009-1016] and oral cancer pain [J Dent Res 91(5):447-453, 2012],skin cancer [Am J Clin Pathol 2004; 122:412-420], cervical cancer[African Journal of Biotechnology Vol. 10(38), pp. 7503-7509, 25 Jul.,2011], bone cancer [J Vet Intern Med 2008; 22:1181-1188]. Other rarecancers such as congenital mesoblastic nephroma, infant fibrosarcoma [AmJ Pathol, 1998; 153:1451-8] and secretory breast carcinoma [Cancer Cell,2002; 347-8] carry Tel-TrkC gene rearrangements. Somatic rearrangementsof TrkA have been detected in a small but consistent subset of papillarythyroid rumors [Cancer Lett 2006; 232:90-8; Mol Cell Endocrinol 2010;321:44-9; Genomics. 1995 Jul. 1; 28(1):15-24; Int J Cancer. 1999 Mar.15; 80(6):842-7].

An exciting new avenue in the field has recently opened with thediscovery of oncogenic TrkA (NTRK1) rearrangements in a small subset oflung cancer patients [Nat Med 2013; 19:1469-72], and in colorectalcancer (as TPM3-TrkA fusion mutation) [Mol Oncol. 2014 Jun. 12. pii:S1574-7891(14)00125-2]. Tumor samples from 3 out of 91 lung cancerpatients without previously identified genetic alterations demonstratedevidence of TrkA gene (NTRK1) fusions. These gene fusion mutations areintracellular oncogenic proteins, and they have constitutive activatedintracellular TrkA kinase activity and transformed fibroblast cells.TrkA (NTRK1), TrkB (NTRK2), or TrkC (NTRK3) fusions have also beenidentified in glioblastoma, spitz tumors, spitzoid melanomas, acutemyelogenous leukemia and secretory breast cancer [Greco A, et al. MolCell Endocrinol 2009; Alberti L, et al. J Cell Physiol 2003;Martin-Zanca D et al. Nature 1986; Wiesner T, et al. Nat Commun 2013;Vaishnavi A, et al, Nat Med 2013]. The identification of this generearrangement or fusion mutations may enable a patient stratificationapproach, similar to that utilized effectively by Pfizer, enabling therapid registration and approval of crizotinib [Drugs 2013; 73:2031-51].

In fact, a patient with TrkA-positive metastatic colorectal cancer wasrecently clinically treated with RXDX-101, a pan Trk inhibitor andachieved a partial response [Ignyta, Inc. News Release. May 31, 2014.Website:http://finance.yahoo.com/news/ignyta-announces-interim-data-rxdx-190000889.html].Our own search of public human cancer genomic databases uncovered thatmany types of human cancers have TrkA fusions or fusion mutations, forexamples, breast cancer (e.g., CAL-51, CAMA-1 and other 3 human breastcancer cells from 5 patients), endometrial cancer (e.g., RK95-2 andother 7 human cancer cells from 8 patients), blood cancer (e.g., CML-T1and other 3 cancer cells from 4 patients), liver cancer (SNU-878 andother 2 cancer cells from 3 patients), colorectal cancer (e.g., SNU-C4and other 10 cancer cells from 11 patients), pancreatic cancer (e.g.,panc 02.13 and panc 03.27 from 2 patients), and skin cancer (e.g., LOXIMVI and other 4 cancer cells from 5 patients), that a TrkA selectiveinhibitor like the ones disclosed in current disclosure or a compound ofthe present disclosure can be utilized to precisely inactiveintracellular TrkA kinase activity in those constitutive activatedintracellular oncogenic proteins, i.e., TrkA fusion mutations, and henceas an effective human cancer treatment therapy for the types of humancancers listed above.

The tyrosine kinase activity of Trk is believed to promote theunregulated activation of cell proliferation machinery. It is believedthat inhibitors of TrkA, TrkB, or TrkC kinases, individually or incombination, have utility against some of the most common cancers suchas brain, melanoma, multiple myeloma, squamous cell, bladder, gastric,pancreatic, breast, head, neck, esophageal, prostate, colorectal, lung,renal, ovarian, gynecological, thyroid cancer, and certain type ofhematological malignancies. Lestaurtinib (CEP-701, Cephalon), anindolocarbazole inhibitor of several tyrosine kinases, including Flt-3and TrkA, and CEP-751, a pan Trk inhibitor have been entered Phase IIclinical trials for the treatment of acute myelogenous leukaemia (AML),pancreatic cancer and multiple myeloma (MM) and/or prostate cancer.

Of particular note are reports of aberrant expression of NGF and TrkAreceptor kinase are implicated in the development and progression ofhuman prostatic carcinoma and pancreatic ductal adenocarcinoma andactivating chromosomal rearrangements of Trks in acute myelogenousleukemia (AML), thyroid and breast cancers and receptor point mutationspredicted to be constitutively activating in colon tumors. In additionto these activation mechanisms, elevated Trk receptor and ligand havealso been reported in a variety of tumor types including multiplemyeloma, melanoma, neuroblastoma, ovarian and pancreatic carcinoma. Theneurotrophins and their corresponding Trk receptor subtypes have beenshown to exert a variety of pleiotropic responses on malignant cells,including enhanced tumor invasiveness and chemotaxis, activation ofapoptosis, stimulation of clonal growth, and altered cell morphology.These effects have been observed in carcinomas of the prostate, breast,thyroid, colon, malignant melanomas, lung carcinomas, glioblastomas,pancreatic carcinoids and a wide variety of pediatric andneuroectodermal-derived tumors including Wilm's tumor, neuroblastomasand medulloblastomas. Neurotrophins and their receptor subtypes havebeen implicated in these cancers either through autocrine or paracrinemechanisms involving carcinoma cells and the surrounding parenchymal andstromal tissues. Overall, the oncogenic properties of Trk signaling inmultiple tumor types makes the modulation of the Trk receptor signalinga potentially attractive therapeutic intervention point in differentmalignancies.

Besides antibodies, however, few TrkA inhibitors are known and very few(if any) show high TrkA kinase selectivity (including staurosporinederived TrkA inhibitors, CEP-751 and CEP-701). It has been rarely (ifany) known in the art that a synthetic organic molecule or compound hadbeen used as either direct TrkA or NGF inhibitor or antagonist fortreatment or prevention of pain in particular. It may due mainly to thefacts of difficulty in identifying potent and particularly selectiveanti-TrkA or anti-NGF small organic compounds, though the crystalstructure of NGF in complex with the TrkA receptor has been determined(Nature 401:184-188 (1996) & 254:411 (1991)).

The therapeutic implications of an effective Trk inhibitor may well gobeyond pain therapy. The subversion of this receptor and its signalingpathway in certain malignancies has also been documented. The tyrosinekinase activity of Trk is believed to promote the unregulated activationof cell proliferation machinery. It is believed that inhibitors of TrkA,TrkB, or TrkC kinases, individually or in combination, have utilityagainst some of the most common cancers such as brain, melanoma,multiple myeloma, squamous cell, bladder, gastric, pancreatic, breast,head, neck, esophageal, prostate, colorectal, lung, renal, ovarian,gynecological, thyroid cancer, and certain type of hematologicalmalignancies. Lestaurtinib (CEP-701, Cephalon), an indolocarbazoleinhibitor of several tyrosine kinases, including Flt-3 and TrkA, andCEP-751, a pan Trk inhibitor have been entered Phase II clinical trialsfor the treatment of acute myelogenous leukemia (AML), pancreatic cancerand multiple myeloma (MM) and/or prostate cancer.

Due to the therapeutic promise associated with inhibiting TrkA, and therelative lack of potent and selective inhibitors, it is great need todiscover the potent and particular isoform selective TrkA inhibitors,especially of orally active small synthetic molecules for possibletreatment or prevention of the disease or disorders associated with TrkAactivity.

3. SUMMARY OF THE DISCLOSURE

The object of the present disclosure is the use of a small syntheticmolecule, and its salts or solvates or prodrug, as protein kinaseinhibitor and/or antagonists, particular as NGF receptor TrkA inhibitorand/or antagonist for the preparation of a medicament for the treatmentand/or prevention of diseases associated directly or indirectly withinhibiting TrkA, which including certain cancer (e.g., pancreaticcancer, gastric cancer, esophageal cancer, gastrointestinal cancer,colorectal cancer, lung (small cell and non-small cell) cancer, livercancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, braincancer or human neuroblastoma, glioblastoma and medulloblastoma,retinoblastoma, leukemia, lymphoma, melanoma, malignant mesothelioma,breast cancer, bladder cancer, ovarian cancer, prostate cancer ormetastasis, thyroid cancer, squamous cell carcinomas, spitz tumors,spitzoid melanomas, acute myelogenous leukemia, endometrial cancer, skincancer, oral cancer, bone cancer, melanoma), itching, atopic dermatitis,scabies, pityriasis, inflammatory bowel disease, inflammatory arthritis,asthma, human airway diseases, respiratory disease, fibrotic disease,renal fibrosis, liver fibrosis, liver cirrhosis, restenosis,atherosclerosis, psoriasis, thrombosis, Chagas' disease, parasiticdiseases, Alzheimer's, pain (i.e, reducing pain for a subject in needthereof, including acute pain, chronic pain, inflammatory pain,neuropathic pain, cancer pain, and generalized pain disorder), PulmonaryInflammatory Diseases, pulmonary sarcoidosis, bladder dysfunction orlower urinary tract dysfunction, Paget's disease, diabetic nephropathy,irritable bowel syndrome, radiation, schizophrenia, a disease, disorder,injury, or malfunction relating to dysmyelination or demyelination orthe disease or disorder associated with abnormal activities of proteinkinases.

In one aspect, the present disclosure provides, among other things,small molecule compounds and their salts or solvates or prodrugs as NGFreceptor TrkA inhibitor and/or antagonist for the preparation of amedicament for the treatment and/or prevention of diseases associated,directly or indirectly with modulation of activity or expression of TrkAprotein kinase or activity in certain patient populations with followingcancer types with TrkA-positive mutations, fusions or fusion mutationsor genetically abnormal TrkA kinase activity, that can be clinicallydiagnosed by current or future diagnostic tools, for examples,pancreatic cancer, prostate cancer or metastasis, breast cancer,hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer,ovarian cancer, thyroid cancer, lung (small cell and non-small cell)cancer, colorectal cancer, glioblastoma, spitz tumors, spitzoidmelanomas, acute myelogenous leukemia, endometrial cancer, skin cancer,oral cancer, bone cancer, melanoma, gastric cancer, esophageal cancer,gastrointestinal cancer, brain cancer or human neuroblastoma,medulloblastoma, retinoblastoma, leukemia, lymphoma, malignantmesothelioma, bladder cancer, squamous cell carcinomas.

In one aspect, the present disclosure provides compounds havingstructural Formula (I):

or a salt, solvate, ester, or prodrug thereof;wherein:

A¹ and A² are independently oxygen or sulfur;

R¹ represents NH₂ or R⁷;

R² represents NR⁷ or CR⁷R¹⁰;

R³, R⁵, R⁶, and R⁹ are independently R⁷;

or alternatively, R⁶ and R⁹, taken together with the atom(s) to whichthey are attached, form a 3 to 6 membered optionally substitutedheteroclcylic group containing one or more heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur;

R⁴ represents halogen, CN, NO₂, CF₃, —(CHR)_(n)COOR¹¹, —(CHR)_(n)SO₂R¹¹,C₁₋₄ haloalkyl, —OC₁₋₄-haloalkyl, C₂₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₈ heterocycle,—(CHR)_(n)C₃₋₈ cycloalkyl, —O—C₆₋₁₀ aryl, —O—C₅₋₁₀ heterocycle,—(CHR)_(n)C(O)CF₃, —(CHR)_(n)C(OH)(CF₃)₂, —(CH₂)_(n)halogen, —OR₁₀,—NR¹¹R¹², —NR^(a)COR¹¹, —NR^(a)COOR¹¹, —NR^(a)SO₂R¹¹, —NR^(a)CONR¹¹R¹²,—COR¹¹, tetrazole, —(CHR)_(n)tetrazole, —S—C₁₋₆ alkyl, or —CONR¹¹R¹²,wherein each said alkyl, alkenyl, alkynyl, aryl, cycloalkyl andheterocycle is independently optionally substituted with 1 to 2 groupsof R⁸;

or alternatively, R⁴ and R⁵, taken together with the atom(s) to whichthey are attached, form a 3 to 6 membered optionally substitutedheteroclcylic group containing one or more heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur;

R⁷ and R¹⁰ are independently selected from the group consisting ofhydrogen, halogen, CN, NH₂, NO₂, C₁₋₄ haloalkyl, —OC₁₋₄ haloalkyl, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₈heterocycle, —(CHR)_(n)C₃₋₈ cycloalkyl, —O—C₆₋₁₀ aryl, —O—C₅₋₁₀heterocycle, —C(O)CF₃, —(CH₂)_(n)halogen, —(CHR)_(n)—(O)_(n)—C(═O)R⁸,—(CHR)_(n)—(S)_(n)—C(═O)R⁸, —OR^(a), —NR¹¹R¹², —NR^(a)COR¹¹,—NR^(a)COOR^(a), —NR^(a)SO₂R, —NR^(a)CONR¹¹R¹², —COR^(a),—(CHR)_(n)COOR^(a), —S—C₁₋₆ alkyl, and —CONR¹¹R¹², wherein each saidalkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle isindependently optionally substituted with 1 to 2 groups of R⁸;

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, N(R^(a))C(═O)R, halogen, CN, NH₂, NHR^(a), NO₂, C₁₋₄haloalkyl, —OC₁₋₄ haloalkyl, C₁₋₆ alkyl, C₂₋₈ alkenyl, —S—C₁₋₆ alkyl,—C(═O)—(O)_(n)—R^(a), —(CHR)_(n)—(O)_(n)—C(═O)R⁸,—(CHR)_(n)—(S)_(n)—C(═O)R⁸, —OR^(a), —(CHR)_(n)C₃₋₁₀ cycloalkyl,—(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₁₀ heteroaryl, and —(CHR)_(n)C₅₋₁₀heterocycle, wherein each said alkyl, alkenyl, cycloalkyl, aryl,heteroaryl and heterocycle is independently optionally substituted with1 to 2 groups of R⁸, and wherein one or more carbon atoms of said alkylmay be replaced with one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur;

or alternatively, R¹¹ and R¹², taken together with the atom(s) to whichthey are attached, form a 3 to 6 membered optionally substitutedheteroclcylic group containing one or more heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur; wherein the optionalsubstituent is R⁸; and

R each independently represents hydrogen, halogen, CN, NO₂, NH₂, or C₁₋₆alkyl;

R^(a) each independently represents hydrogen or C₁₋₆ alkyl;

R⁸ each independently represents C₁₋₆ alkyl, halogen, CN, NO₂, NH₂,NHR^(a), SO₂R¹¹, or NR^(a)SO₂R¹¹; and

n represents an integer from 0 to 3;

with the following provisos:

when R² is CH₂, R⁴ is not H or CH₃;

when R² is NCH₂CH₂OH, (a) R⁴ is not H or OCH₃, or (b) R⁵ is not OCH₃;and

when R² is N(CH₃), R⁴ is not H, CH₃, OCH₃, or F.

In one embodiment of formula (I), R¹ is selected from the groupconsisting of hydrogen, —(CH₂)_(n)halogen, —CN, —CH₃, NH₂, NHR^(a), and—C₁₋₃ alkyl.

In one embodiment of formula (I), R⁴ is selected from the groupconsisting of —C(O)OR¹¹, —SO₂NHC(═O)CH₃, —C(CF₃)(CF₃)OH, —SO₂NH₂,—C(O)NR¹¹R¹², —CN, —CF₃, —NO₂, —C(O)CF₃, (CH₂)_(n)halogen,

In one embodiment of formula (I), R³, R⁵, R⁶, and R⁹ are hydrogen.

In one embodiment of formula (I), R² is selected from

In another aspect, the present disclosure provides compounds havingstructural Formula (II):

or a salt, solvate, ester, or prodrug thereof;wherein:

X represents N or CH;

R⁴ represents carboxy bioisostere selected from —(CHR)_(n)COOR¹¹,—(CHR)_(n)SO₂R¹¹, —(CHR)_(n)C₅₋₈ heterocycle, or —(CHR)_(n)C(OH)(CF₃)₂,wherein each said heterocycle is independently optionally substitutedwith 1 to 2 groups of R⁸;

R¹¹ is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, NH₂, NHR^(a), and NR^(a)C(═O)R wherein each said alkyl isindependently optionally substituted with 1 to 2 groups of R⁸, andwherein one carbon atom of said alkyl may be replaced with oneheteroatom selected from the group consisting of nitrogen, oxygen, andsulfur;

R⁸ each independently represents C₁₋₆ alkyl, halogen, CN, NO₂, NH₂,NHR^(a), SO₂R¹¹, or NR^(a)SO₂R¹¹;

R each independently represents hydrogen, halogen, CN, NO₂, NH₂, or C₁₋₆alkyl;

R^(a) each independently represents hydrogen or C₁₋₆ alkyl; and

n represents 0.

In one embodiment of formula (II), X represents N.

In one embodiment of formula (II), R⁴ represents —COOR¹¹, wherein R¹¹ ishydrogen. In one embodiment of formula (II), R⁴ represents —COOR¹¹,wherein R¹¹ is C₁₋₆ alkyl. In some embodiments of formula (II), R⁴represents —COOR¹¹, wherein R¹¹ is C₁₋₆ alkyl where one carbon atom ofsaid C₁₋₆ alkyl is replaced with one nitrogen atom.

In one embodiment of formula (II), X represents N and R⁴ represents—COOR¹¹, wherein R¹¹ is hydrogen.

In another embodiment of formula (II), R⁴ represents —SO₂R¹¹, whereinR¹¹ is NH₂ or NR^(a)C(═O)R. In some embodiments of formula (II), R⁴represents —SO₂R¹¹, wherein R¹¹ is NHC(═O)R and wherein R is C₁₋₆ alkyl.

In one embodiment of formula (II), R⁴ represents C₅ heterocycle, whereinthe heterocycle is a tetrazole.

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising one or more compounds as described above or asalt, solvate, ester, prodrug, or physiologically functional derivativethereof; and a pharmaceutically acceptable vehicle.

In still another aspect, the present disclosure provides methods forselectively inhibiting or antagonizing NGF receptor TrkA for treatmentand/or prevention of certain disease, disorder, symptom or conditionincluding cancer (e.g., pancreatic cancer, gastric cancer, esophagealcancer, gastrointestinal cancer, colorectal cancer, lung cancer, livercancer, brain cancer or human neuroblastoma, glioblastoma andmedulloblastoma, retinoblastoma, leukemia, lymphoma, melanoma, malignantmesothelioma, breast cancer, bladder cancer, ovarian cancer, prostatecancer, thyroid cancer, squamous cell carcinomas, itching, atopicdermatitis, scabies, pityriasis, inflammatory bowel disease,inflammatory arthritis, asthma, human airway diseases, restenosis,atherosclerosis, psoriasis, thrombosis, Chagas' disease, parasiticdiseases, Alzheimer's, pain, a disease, disorder, injury, or malfunctionrelating to dysmyelination or demyelination or the disease or disorderassociated with abnormal activities of protein kinases, with therapeuticeffective amount of the compound as described above, or a salt, solvate,or physiologically functional derivative thereof.

In still another aspect, the present disclosure provides methods fortreatment and/or prevention of certain cancer (e.g., pancreatic cancer,gastric cancer, esophageal cancer, gastrointestinal cancer, colorectalcancer, lung cancer, liver cancer, brain cancer or human neuroblastoma,glioblastoma and medulloblastoma, retinoblastoma, leukemia, lymphoma,melanoma, malignant mesothelioma, breast cancer, bladder cancer, ovariancancer, prostate cancer, thyroid cancer, squamous cell carcinomas,itching, atopic dermatitis, scabies, pityriasis, inflammatory boweldisease, inflammatory arthritis, asthma, human airway diseases,restenosis, atherosclerosis, psoriasis, thrombosis, Chagas' disease,parasitic diseases, Alzheimer's, pain, a disease, disorder, injury, ormalfunction relating to dysmyelination or demyelination or the diseaseor disorder associated with abnormal activities of protein kinases, withcombination of (a) therapeutic effective amount of the compound asdescribed above, or a salt, solvate, or ester, prodrug, orphysiologically functional derivative thereof, and either (b1) an opioidanalgesic or at least one analgesic agent that acts by a mechanismdifferent from a TrkA antagonist or (b2) an existing or provedanti-cancer agent or at least one existing or proved anti-cancer agent.

Additional embodiments include a combination of any of the foregoingembodiments and one or more pharmaceutically acceptable excipients.Other embodiments include a dosage form, such as a solid or semi-soliddosage form, comprising any of the foregoing crystal forms, amorphousforms, or combinations. In yet other embodiments, a dosage formcomprising any of the foregoing crystal forms, amorphous forms, orcombinations comprises one or more of a tablet, hard capsule, softcapsule, powder, suppository, and gel, or one or more of an injectableform, a transdermal patch, a sprayable form, and an implantable depot.

Other embodiments are a use of any of the foregoing embodiments inmaking a dosage form for inhibiting, or for inhibiting, a NGF receptor,TrkA. Still other embodiments are a use of any of the foregoingembodiments in making a dosage form for treating a disorder, disease orcondition selected from the group consisting of pain (i.e, reducing painfor a subject in need thereof, including acute pain, chronic pain,inflammatory pain, neuropathic pain, cancer pain, and generalized paindisorder), cancer (e.g., pancreatic cancer, prostate cancer ormetastasis, breast cancer, hepatocellular carcinoma, intrahepaticcholangiocarcinoma, liver cancer, ovarian cancer, thyroid cancer, lung(small cell and non-small cell) cancer, colorectal cancer, glioblastoma,spitz tumors, spitzoid melanomas, acute myelogenous leukemia,endometrial cancer, skin cancer, oral cancer, bone cancer, melanoma,gastric cancer, esophageal cancer, gastrointestinal cancer, brain canceror human neuroblastoma, medulloblastoma, retinoblastoma, leukemia,lymphoma, malignant mesothelioma, bladder cancer, squamous cellcarcinomas), atopic dermatitis, psoriasis, skin diseases, itch, liverfibrosis, liver cirrhosis, scabies, pityriasis, inflammatory boweldisease, inflammatory arthritis, asthma, human airway diseases, Chagas'disease, parasitic diseases, Alzheimer's, restenosis, atherosclerosis,thrombosis, liver cirrhosis, liver fibrosis, Pulmonary InflammatoryDiseases, pulmonary sarcoidosis, bladder dysfunction or lower urinarytract dysfunction, Paget's disease, diabetic nephropathy, irritablebowel syndrome, radiation, schizophrenia, or a disease, disorder orinjury relating to dysmyelination or demyelination or the disease ordisorder associated with abnormal activities of TrkA protein kinases orfusions or mutations of TrkA (NTRK1) protein, with therapeutic effectiveamount of the compound as described above, or a salt, solvate, orphysiologically functional derivative thereof.

In another aspect, the disclosure provides pharmaceutical compositionscomprising the compound described above, and a pharmaceuticallyacceptable vehicle.

In another aspect, the disclosure provides a method of use of a compoundhaving structural Formula (I) and/or Formula (II) in medical treatmentand prevention.

In another aspect, the disclosure provides a method of use of a compoundhaving structural Formula (I) and/or Formula (II) in medical treatmentand prevention of pain (i.e, reducing pain for a subject in needthereof, including acute pain, chronic pain, inflammatory pain,neuropathic pain, cancer pain, and generalized pain disorder), cancer(e.g., pancreatic cancer, prostate cancer or metastasis, breast cancer,hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer,ovarian cancer, thyroid cancer, lung (small cell and non-small cell)cancer, colorectal cancer, glioblastoma, spitz tumors, spitzoidmelanomas, acute myelogenous leukemia, endometrial cancer, skin cancer,oral cancer, bone cancer, melanoma, gastric cancer, esophageal cancer,gastrointestinal cancer, brain cancer or human neuroblastoma,medulloblastoma, retinoblastoma, leukemia, lymphoma, malignantmesothelioma, bladder cancer, squamous cell carcinomas), atopicdermatitis, psoriasis, skin diseases, itch, liver fibrosis, livercirrhosis, scabies, pityriasis, inflammatory bowel disease, inflammatoryarthritis, asthma, human airway diseases, Chagas' disease, parasiticdiseases, Alzheimer's, restenosis, atherosclerosis, thrombosis, livercirrhosis, liver fibrosis, Pulmonary Inflammatory Diseases, pulmonarysarcoidosis, bladder dysfunction or lower urinary tract dysfunction,Paget's disease, diabetic nephropathy, irritable bowel syndrome,radiation, schizophrenia, or a disease, disorder or injury relating todysmyelination or demyelination or the disease or disorder associatedwith abnormal activities of TrkA protein kinases or fusions or mutationsof TrkA (NTRK1) protein, with combination of (a) therapeutic effectiveamount of the compound as described above, or a salt, solvate, or ester,prodrug, or physiologically functional derivative thereof, and either(b1) an opioid analgesic or at least one analgesic agent that acts by amechanism different from a Trk antagonist or, (b2) an existing orapproved anti-cancer agent or chemotherapeutic or at least one existingor approved anti-cancer agent.

In another aspect, the disclosure provides a method for preparing acompound having structural Formula (I) and/or Formula (II) describedabove.

In another aspect, the disclosure provides a method for treating adisease, disorder, symptom, or condition associated with irregular TrkAactivity, or fusion or mutation of TrkA protein or NTRK1 gene in apatient suffering therefrom, comprising administering to the patient apharmaceutical composition, comprising a therapeutically effectiveamount of a compound having structural Formula (I) and/or Formula (II),wherein the pharmaceutical composition is formulated in a unit dosageform selected from the group consisting of: an oral unit dosage form(including powder, tablets, pills, pellets, capsules, powders, lozenges,granules, solutions, suspensions, emulsion, syrups, elixirs,sustained-release formulations, aerosols, sprays and caplet), aninhalational unit dosage form (including spray, aerosol, inhaler,neulizer, smoking and vaporizer), a parenteral unit dosage form(including intradermal, intramuscular, intraosseous, intraperitoneal,intravenous, epidural, intracardiac, intraocular, intra-articular,subcutaneous and intrathecal injection unit dosage forms), a topicalunit dosage form (including cream, gel, liniment or balm, lotion orointment, ear drops, eye drops, skin patch and vaginal rings), anintranasal unit dosage form, a suppository unit dosage form (includingvaginal, douche, pessary, and rectal), an epidural unit dosage form, asublingual unit dosage form (including lozenge and troche), and anintracerebral unit dosage form.

In another aspect, the disclosure provides a method for treating adisease, disorder, symptom, or condition associated with irregular TrkAactivity, or fusion or mutation of TrkA protein or NTRK1 gene in apatient suffering therefrom, comprising administering to the patient apharmaceutical composition, comprising a therapeutically effectiveamount of a compound having structural Formula (I) and/or Formula (II),wherein the pharmaceutical composition is formulated in an oral unitdosage form comprising from about 0.02 mg of the compound per kg of bodyweight to about 60 mg of the compound per kg of body weight.

In another aspect, the disclosure provides a method for treating adisease, disorder, symptom, or condition associated with irregular TrkAactivity, or fusion or mutation of TrkA protein or NTRK1 gene in apatient suffering therefrom, comprising administering to the patient apharmaceutical composition, comprising a therapeutically effectiveamount of a compound having structural Formula (I) and/or Formula (II),wherein the pharmaceutical composition is formulated in an intravenousunit dosage form comprising from about 0.002 mg of the compound per kgof body weight to about 60 mg of the compound per kg of body weight.

In another aspect, the disclosure provides a method for treating adisease, disorder, symptom, or condition associated with irregular TrkAactivity, or fusion or mutation of TrkA protein or NTRK1 gene in apatient suffering therefrom, comprising administering to the patient apharmaceutical composition, comprising a therapeutically effectiveamount of a compound having structural Formula (I) and/or Formula (II),wherein the pharmaceutical composition is formulated in an intranasalunit dosage form comprising from about 0.002 mg of the compound per kgof body weight to about 6 mg of the compound per kg of body weight.

In another aspect, the disclosure provides a method for treating adisease, disorder, symptom, or condition associated with irregular TrkAactivity, or fusion or mutation of TrkA protein or NTRK1 gene in apatient suffering therefrom, comprising administering to the patient apharmaceutical composition, comprising a therapeutically effectiveamount of a compound having structural Formula (I) and/or Formula (II),wherein the pharmaceutical composition is formulated in a suppositoryunit dosage form comprising from about 0.001 mg of the compound per kgof body weight to about 50 mg of the compound per kg of body weight andcomprise active ingredient in the range of about 0.5% to about 10% byweight.

In another aspect, the disclosure provides a method for treating adisease, disorder, symptom, or condition associated with irregular TrkAactivity, or fusion or mutation of TrkA protein or NTRK1 gene in apatient suffering therefrom, comprising administering to the patient apharmaceutical composition, comprising a therapeutically effectiveamount of a compound having structural Formula (I) and/or Formula (II),wherein the pharmaceutical composition is formulated in a unit dosageform selected from the group consisting of: a parenteral unit dosageform (including intradermal, intramuscular, intraosseous,intraperitoneal, intravenous, epidural, intracardiac, intraocular,intra-articular, subcutaneous and intrathecal injection unit dosageforms), a topical unit dosage form (including cream, gel, liniment orbalm, lotion or ointment, ear drops, eye drops, skin patch and vaginalrings), an intranasal unit dosage form, a suppository unit dosage form(including vaginal, douche, pessary, and rectal), an epidural unitdosage form, a sublingual unit dosage form (including lozenge andtroche), and an intracerebral unit dosage form, an intradermal unitdosage form, an intramuscular unit dosage form, an intraperitoneal unitdosage form, a subcutaneous unit dosage form, an epidural unit dosageform, a sublingual unit dosage form, and an intracerebral unit dosageform, wherein said unit dosage forms comprise from about 0.001 mg of thecompound per kg of body weight to about 60 mg of the compound per kg ofbody weight.

5. DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure relates to novel synthetic small molecules thatact as inhibitors and/or antagonists of the members of Trk familyprotein kinases, in particularly the NGF receptor, TrkA.

5.1 Definitions

Terms used in the claims and specification are defined as set forthbelow unless otherwise specified.

The term “a compound of the present disclosure”, “the compound of thepresent disclosure”, “compounds of the present disclosure”, or “thepresent compounds” refers to one or more compounds encompassed by thestructural formulae and/or any subgeneric formulae disclosed herein andincludes any specific compounds within these generic formula whosestructure is disclosed herein. Compounds of the disclosure may containone or more chiral centers and/or double bonds and therefore, may existas stereoisomers, such as double-bond isomers (i.e., geometric isomers),the racemic mixtures, enantiomers or diastereomers. Accordingly, thechemical structures depicted herein encompass all possible enantiomersand stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. The compounds of the disclosure may also exist in severaltautomeric forms. Accordingly, the chemical structures depicted hereinencompass all possible tautomeric forms of the illustrated compounds.Compounds also include isotopically labeled compounds where one or moreatoms have an atomic mass different from the atomic mass conventionallyfound in nature. Examples of isotopes that may be incorporated into thecompounds include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O,¹⁸O, etc. Compounds may exist in unsolvated forms as well as solvatedforms, including hydrated forms and as N-oxides. In general, the salt,hydrated, solvated, and N-oxide forms are within the scope of thepresent disclosure. Certain compounds of the present disclosure mayexist in multiple crystalline forms or an amorphous form. In general,all physical forms are equivalent for the uses contemplated by thepresent disclosure and are intended to be within the scope of thepresent disclosure.

The term “physiologically functional derivative(s)” used herein refersto any physiologically tolerated derivative of a compound of the presentdisclosure, for example, an ester or prodrug, which, upon administrationto a mammal, e.g., a human, are transformed directly or indirectly to acompound of formula (I) and/or formula (II), or an active metabolitethereof. Physiologically functional derivatives include prodrugs of thecompounds of the present disclosure. Examples of prodrug are describedin H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugscan be metabolized in vivo to a compound of the disclosure. Theseprodrugs may themselves be active or not.

“Alkyl” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. The term“alkyl” is specifically intended to include groups having any degree orlevel of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl). Typical alkyl groups include, but are notlimited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl;cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkanyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkyldiyl” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group derived by the removal of one hydrogen atom from eachof two different carbon atoms of a parent alkane, alkene or alkyne, orby the removal of two hydrogen atoms from a single carbon atom of aparent alkane, alkene or alkyne. The two monovalent radical centers oreach valency of the divalent radical center can form bonds with the sameor different atoms. Typical alkyldiyl groups include, but are notlimited to methandiyl; ethyldiyls such as ethan-1,1-diyl,ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such aspropan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl,cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl,prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl,cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Insome embodiments, the alkyldiyl group is (C₁-C₂₀) alkyldiyl, morepreferably, (C₁-C₁₀) alkyldiyl, most preferably, (C₁-C₆) alkyldiyl.

“Alkyleno” by itself or as part of another substituent, refers to astraight-chain alkyldiyl group having two terminal monovalent radicalcenters derived by the removal of one hydrogen atom from each of the twoterminal carbon atoms of straight-chain parent alkane, alkene or alkyne.Typical alkyleno groups include, but are not limited to, methano;ethylenos such as ethano, etheno, ethyno; propylenos such as propano,prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenos such as butano,but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno,but[1,3]diyno, etc.; and the like. Where specific levels of saturationare intended, the nomenclature alkano, alkeno and/or alkyno is used.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R²⁰⁰, where R²⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Amino” by itself or as part of another substituent refers to a radical—NR^(a)R^(b), where R^(a) and R^(b) are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl orsubstituted heteroarylalkyl as defined herein, or alternatively R^(a)and R^(b), taken together with the atoms to which they are bonded, forma cycloheteroalkyl ring. Representative examples include, but are notlimited to —NH₂, —NHCH₃, —N(CH₃)₂, —NH-phenyl, —NH—CH₂-phenyl,pyrrolidine, and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 10 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. Typical arylalkyl groups include,but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyland/or arylalkynyl is used. In some embodiments, an arylalkyl group is(C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₅)alkyl and the aryl moiety is (C₆-C₁₂) aryl. In still other embodiments,an arylalkyl group is (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₆-C₁₀) aryl.

“Aryloxy,” by itself or as part of another substituent, refers to aradical of the formula —O—R²⁰¹, where R²⁰¹ is aryl, substituted aryl,arylalkyl, or substituted arylalkyl.

“Aryloxycarbonyl,” by itself or as part of another substituent, refersto a radical of the formula —C(O)—O—R²⁰¹, where R²⁰¹ is aryl,substituted aryl, arylalkyl, or substituted arylalkyl.

“Carboxy bioisostere,” by itself or as part of another substituent, asused herein refers to a moiety that at physiological pH is expected toproduce similar chemical or biological properties of a moiety ofcarboxylic acid at the same position of the compound. In certainembodiments, the carboxylate bioisostere is a moiety selected from thegroup consisting of —C(O)OR¹¹, —SO₂R¹¹, —C₅₋₈ heterocycle, and—C(OH)(CF₃)₂; R¹¹ is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, NH₂, NHR^(a), and NR^(a)C(═O)R wherein each saidalkyl is independently optionally substituted, and wherein one carbonatom of said alkyl may be replaced with one heteroatom selected from thegroup consisting of nitrogen, oxygen, and sulfur; R each independentlyrepresents hydrogen, halogen, CN, NO₂, NH₂, or C₁₋₆ alkyl; R^(a) eachindependently represents hydrogen or C₁₋₆ alkyl.

“Cycloalkyl” or “carbocyclyl” by itself or as part of anothersubstituent, refers to a saturated or unsaturated cyclic alkyl radical,as defined herein. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typicalcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Insome embodiments, a cycloalkyl group comprises from 3 to 10 ring atoms(C₃-C₁₀ cycloalkyl). In other embodiments, a cycloalkyl group comprisesfrom 3 to 7 ring atoms (C₃-C₇ cycloalkyl).

“Cycloheteroalkyl” or “heterocyclyl” by itself or as part of anothersubstituent, refers to a saturated or unsaturated cyclic alkyl radicalin which one or more carbon atoms (and optionally any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Typical heteroatoms to replace the carbon atom(s) include,but are not limited to, B, N, P, O, S, Si, etc. Where a specific levelof saturation is intended, the nomenclature “cycloheteroalkanyl” or“cycloheteroalkenyl” is used. Typical cycloheteroalkyl groups include,but are not limited to, groups derived from epoxides, azirines,thiiranes, imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidone, quinuclidine, borolane, dioxaborolane, andthe like. In some embodiments, the cycloheteroalkyl group comprises from3 to 10 ring atoms (3-10 membered cycloheteroalkyl). In otherembodiments, the cycloalkyl group comprise from 5 to 7 ring atoms (5-7membered cycloheteroalkyl).

“Halogen” or “halo” by itself or as part of another substituent, refersto any of the elements fluorine, chlorine, bromine, iodine, andastatine, occupying group VIIA (17) of the periodic table.

A cycloheteroalkyl group may be substituted at a heteroatom, forexample, a nitrogen atom, with a (C₁-C₆) alkyl group. As specificexamples, N-methyl-imidazolidinyl, N-methyl-morpholinyl,N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl andN-methyl-pyrrolidinyl are included within the definition of“cycloheteroalkyl.” A cycloheteroalkyl group may be attached to theremainder of the molecule via a ring carbon atom or a ring heteroatom.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkanyl,Heteroalkyldiyl and Heteroalkyleno” by themselves or as part of anothersubstituent, refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl andalkyleno groups, respectively, in which one or more of the carbon atoms(and any associated hydrogen atoms) are each independently replaced withthe same or different heteroatomic groups. Typical heteroatomic groupswhich can be included in these groups include, but are not limited to,—O—, —S—, —O—O—, —S—S—, —O—S—, —NR²⁰³R²⁰⁴—, ═N—N═, —N═N—,—N═N—NR²⁰⁵R²⁰⁶, —PR²⁰⁷—, —P(O)₂—, —POR²⁰⁸—, —O—P(O)₂—, —SO—, —SO₂—,—SnR²⁰⁹R²¹⁰—, —BR²¹¹R²¹², BOR²¹³OR²¹⁴ and the like, where R²⁰³, R²⁰⁴,R²⁰⁵, R²⁰⁶, R²⁰⁷, R²⁰⁸, R²⁰⁹, R²¹⁰, R²¹¹, R²¹², R²¹³ and R²¹⁴ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,furopyridine, and the like. In some embodiments, the heteroaryl groupcomprises from 5 to 20 ring atoms (5-20 membered heteroaryl). In otherembodiments, the heteroaryl group comprises from 5 to 10 ring atoms(5-10 membered heteroaryl). Exemplary heteroaryl groups include thosederived from furan, thiophene, pyrrole, benzothiophene, benzofuran,benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole,oxazole, isoxazole and pyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Heteroaryloxy,” by itself or as part of another substituent, refers toa radical of the formula —O—R²⁰¹, where R²⁰¹ is heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

“Heteroaryloxycarbonyl,” by itself or as part of another substituent,refers to a radical of the formula —C(O)—O—R²⁰¹, where R²⁰¹ isheteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

“Modulating” refers to adjusting, varying, or changing. As used herein,modulation of calcium ion channel includes antagonizing, agonizing, orpartially antagonizing. That is, the compounds of the present disclosuremay act as antagonists, agonists, or partial antagonists of the calciumion channel activity.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms (and optionally any associatedhydrogen atoms) are each independently replaced with the same ordifferent heteroatom. Typical heteroatoms to replace the carbon atomsinclude, but are not limited to, B, N, P, O, S, Si, etc. Specificallyincluded within the definition of “parent heteroaromatic ring system”are fused ring systems in which one or more of the rings are aromaticand one or more of the rings are saturated or unsaturated, such as, forexample, benzodioxan, benzofuran, chromane, chromene, indole, indoline,xanthene, etc. Typical parent heteroaromatic ring systems include, butare not limited to, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene and the like.

“Patient” or “subject” includes, but is not limited to animals such as,for example, mammals. Preferably, the patient is a human.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Solvate” means a compound formed by solvation (the combination ofsolvent molecules with molecules or ions of the solute, i.e., a compoundof the present disclosure), or an aggregate that consists of a soluteion or molecule (the compound of the present disclosure) with one ormore solvent molecules.

“Pharmaceutically acceptable” means suitable for use in contact with thetissues of humans and animals without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use within thescope of sound medical judgment.

“Prodrug or softdrug” refers to a precursor of a pharmaceutically activecompound wherein the precursor itself may or may not be pharmaceuticallyactive but, upon administration, will be converted, either metabolicallyor otherwise, into the pharmaceutically active compound or drug ofinterest. For example, prodrug or softdrug is an ester or an ether formof a pharmaceutically active compound. Several prodrugs have beenprepared and disclosed for a variety of pharmaceuticals. See, forexample, Bundgaard, H. and Moss, J., J. Pharm. Sci. 78: 122-126 (1989).Thus, one of ordinary skill in the art knows how to prepare theseprecursors, prodrugs or softdrugs with commonly employed techniques oforganic synthesis.

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halogen, —O⁻, ═O, —OR^(b), —SR^(b), —S—, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O—, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O—, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O—,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, arylalkyl, alkyldiyl,substituted alkyldiyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroalkyldiyl,substituted heteroalkyldiyl, heteroaryl, substituted heteroaryl,heteroarylalkyl substituted heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s are taken together with the nitrogen atomto which they are bonded form a cycloheteroalkyl ring which mayoptionally include from 1 to 4 of the same or different additionalheteroatoms selected from the group consisting of O, N and S. Asspecific examples, —NR^(c)R^(c) is meant to include —NH₂, —NH-alkyl,N-pyrrolidinyl and N-morpholinyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halogen, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c),trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b),—S(O)₂O—, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O—, —OS(O)₂OR^(b),—P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b),—C(S)R^(b), —C(NR^(b))R^(b), —C(O)O—, —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a), R^(b) and R^(c) are aspreviously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O⁻, —OR^(b), —SR^(b), —S—, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R^(b), —S(O)₂O—, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O—,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups from the above lists useful for substituting otherspecified groups or atoms will be apparent to those of skill in the art.The substituents used to substitute a specified group can be furthersubstituted, typically with one or more of the same or different groupsselected from the various groups specified above. The term “optionallysubstituted”, when used with a specific group, means the specific groupcan be substituted or unsubstituted. For example, an optionallysubstituted alkyl denotes a substituted alkyl or unsubstituted alkyl.

“Treating”, “treat” or “treatment” of any disease or disorder refers, insome embodiments, to ameliorating or preventing the disease or disorder(i.e., arresting, preventing, holding or reducing the development of thedisease or at least one of the clinical symptoms thereof). In otherembodiments “treating”, “treat” or “treatment” refers to ameliorating atleast one physical parameter, which may not be discernible by thepatient. In yet other embodiments, “treating”, “treat” or “treatment”refers to inhibiting, or holding or preventing the progress of, thedisease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter) or both. In yet other embodiments, “treating”,“treat” or “treatment” refers to delaying the onset of the disease ordisorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the patient to be treated.

“Vehicle” refers to a diluent, adjuvant, excipient or carrier with whicha compound is administered.

Reference will now be made in detail to preferred embodiments of thedisclosure. While the disclosure will be described in conjunction withthe preferred embodiments, it will be understood that it is not intendedto limit the disclosure to those preferred embodiments. To the contrary,it is intended to cover alternatives, modifications, and equivalents asmay be included within the spirit and scope of the disclosure as definedby the appended claims.

The term “receptor” refers to a molecule or complex of molecules,typically (although not necessarily) a protein(s), that is specificallybound by one or more particular ligands. The receptor is said to be areceptor for such ligand(s). Ligand-receptor binding, in many instances,induces one or more biological responses. A “modulator” of a polypeptideis either an inhibitor or an enhancer of an action or function of thepolypeptide. Similarly, a “modulator” of a signaling pathway is aninhibitor or enhancer of at least one function mediated by the signalingpathway. Aspects of modulators are defined below with respect topolypeptides; however, those of skill in the art readily appreciate thatthese definitions also apply to signaling pathways.

A “non-selective” modulator of a polypeptide is an agent that modulatesother members of the same family of polypeptides at the concentrationstypically employed for modulation of the particular polypeptide.

A “selective” modulator of a polypeptide significantly modulates theparticular polypeptide at a concentration at which other members of thesame family of polypeptides are not significantly modulated.

A modulator “acts directly on” a polypeptide when the modulator exertsits action by interacting directly with the polypeptide.

A modulator “acts indirectly on” a polypeptide when the modulator exertsits action by interacting with a molecule other than the polypeptide,which interaction results in modulation of an action or function of thepolypeptide.

An “inhibitor” or “antagonist” of a polypeptide is an agent thatreduces, by any mechanism, any action or function of the polypeptide, ascompared to that observed in the absence (or presence of a smalleramount) of the agent. An inhibitor of a polypeptide can affect: (1) theexpression, mRNA stability, protein trafficking, modification (e.g.,phosphorylation), or degradation of a polypeptide, or (2) one or more ofthe normal action or functions of the polypeptide. An inhibitor of apolypeptide can be non-selective or selective. Preferred inhibitors(antagonists) are generally small molecules that act directly on, andare selective for, the target polypeptide.

A “reversible” inhibitor is one whose effects can be reversed (i.e., onethat does not irreversibly inactivate the target polypeptide).

A “competitive” inhibitor of a polypeptide is one that competes forbinding to the polypeptide with another component required forpolypeptide function. For example, TrkA function requires the binding ofATP and substrate. Accordingly, a competitive inhibitor of TrkA can act,for example, by binding at the ATP or substrate binding sites. Thisinhibition is generally reversible by increasing the concentration ofATP or substrate to the reaction mixture. Such an inhibitor is said toinhibit TrkA competitively with respect to ATP or substrate,respectively.

A “non-competitive” inhibitor of a polypeptide generally binds thepolypeptide at a site other than the binding site of another componentrequired for polypeptide function. This inhibition cannot be reversed byincreasing the concentration of component(s) required for polypeptidefunction.

As used herein, an “allosteric modulator” of an polypeptide, typicallyan enzyme or receptor, is a modulator that binds at a location otherthan the active site of the target polypeptide, altering activity byinducing an allosteric change in the shape of the target polypeptide.

The terms “polypeptide” and “protein” are used interchangeably herein torefer a polymer of amino acids, and unless otherwise limited, includeatypical amino acids that can function in a similar manner to naturallyoccurring amino acids.

The term “specific binding” is defined herein as the preferentialbinding of binding partners to another (e.g., two polypeptides, apolypeptide and nucleic acid molecule, or two nucleic acid molecules) atspecific sites. The term “specifically binds” indicates that the bindingpreference (e.g., affinity) for the target molecule/sequence is at least2-fold, more preferably at least 5-fold, and most preferably at least10- or 20-fold over a non-specific target molecule (e.g. a randomlygenerated molecule lacking the specifically recognized site(s)).

The phrases “an effective amount” and “an amount sufficient to” refer toamounts of a biologically active agent that produce an intendedbiological activity.

The term “co-administer” or “co-administering” when used in reference tothe administration of Trk (i.e., TrkA) antagonists and other agentsindicates that the antagonist and other agent(s) are administered in acoordinated fashion so that there is at least some chronological overlapin their physiological activity on the subject. Thus, a TrkA antagonistcan be administered simultaneously and/or sequentially with anotheragent. In sequential administration, there may even be some substantialdelay (e.g., minutes or even hours or days) before administration of thesecond agent as long as the first administered agent is exerting somephysiological effect on the organism when the second administered agentis administered or becomes active in the subject.

The term “reducing pain”, as used herein, refers to decreasing the levelof pain a subject perceives relative to the level of pain the subjectwould have perceived were it not for the intervention. Where the subjectis a person, the level of pain the person perceives can be assessed byasking him or her to describe the pain or compare it to other painfulexperiences. Alternatively, pain levels can be determined by measuringthe subject's physical responses to the pain, such as the release ofstress-related factors or the activity of pain-transducing nerves in theperipheral nervous system or the CNS. One can also determine pain levelsby measuring the amount of a well-characterized analgesic required for aperson to report that no pain is present or for a subject to stopexhibiting symptoms of pain. A reduction in pain can also be measured asan increase in the threshold at which a subject experiences a givenstimulus as painful. In certain embodiments, a reduction in pain isachieved by decreasing “hyperalgesia,” the heightened sensitivity to anoxious stimulus, and such inhibition can occur without impairing“nociception,” the subject's normal sensitivity to a “noxious” stimulus.The term “pain”, as used herein, refers also to, for examples, acutepain, chronic pain, inflammatory pain, neuropathic pain, and generalizedpain disorder.

As used with reference to pain reduction, “a subject in need thereof”refers to an animal or person, preferably a person, expected toexperience pain in the near future. Such animal or person may have anongoing condition that is causing pain currently and is likely tocontinue to cause pain. Alternatively, the animal or person has been,is, or will be enduring a procedure or event that usually has painfulconsequences. Chronic painful conditions such as diabetic neuropathichyperalgesia and collagen vascular diseases are examples of the firsttype; dental work, particularly that accompanied by inflammation ornerve damage, and toxin exposure (including exposure to chemotherapeuticagents) are examples of the latter type.

“Inflammatory pain” refers to pain arising from inflammation.Inflammatory pain often manifests as increased sensitivity to mechanicalstimuli (mechanical hyperalgesia or tenderness). For examples,inflammatory pain is due to a condition selected from the groupconsisting of: burn, sunburn, arthritis, osteoarthritis, colitis,carditis, dermatitis, myositis, neuritis, mucositis, urethritis,cystitis, gastritis, pneumonitis, and collagen vascular disease.

“Neuropathic pain” refers to pain arising from conditions or events thatresult in nerve damage. “Neuropathy” refers to a disease processresulting in damage to nerves. “Causalgia” denotes a state of chronicpain following nerve injury. “Allodynia” refers to a condition in whicha person experiences pain in response to a normally nonpainful stimulus,such as a gentle touch. For examples, neuropathic pain is due to acondition selected from the group consisting of: causalgia, diabetes,diabetic peripheral neuropathy, collagen vascular disease, trigeminalneuralgia, spinal cord injury, brain stem injury, thalamic painsyndrome, complex regional pain syndrome type I/reflex sympatheticdystrophy, Fabry's syndrome, small fiber neuropathy, cancer, cancerchemotherapy, chronic alcoholism, stroke, abscess, demyelinatingdisease, viral infection, anti-viral therapy, AIDS, and AIDS therapy.Neuropathic pain is due to an agent selected from the group consistingof: trauma, surgery, amputation, toxin, and chemotherapy.

As used herein, the term “generalized pain disorder” refers to a groupof idiopathic pain syndromes (e.g., fibromyalgia, irritable bowelsyndrome, and temporomandibular disorders), for which the pathogenicmechanism is currently unknown, characterized by diffuse or generalizedpain, and for which a diagnosis of inflammation or neuropathy as thedirect cause of pain is excluded.

An “analgesic agent” refers to a molecule or combination of moleculesthat causes a reduction in pain.

The difference between “acute” and “chronic” pain is one of timing:acute pain is experienced soon (e.g., generally within about 48 hours,more typically within about 24 hours, and most typically within about 12hours) after the occurrence of the event (such as inflammation or nerveinjury) that led to such pain. By contrast, there is a significant timelag between the experience of chronic pain and the occurrence of theevent that led to such pain. Such time lag is generally at least about48 hours after such event, more typically at least about 96 hours aftersuch event, and most typically at least about one week after such event.

The term “maladaptive substance use” refers to the use of any substancethat results in adverse consequences for the user that outweigh anybenefits derived from the substance. Substances that are used in amaladaptive manner are generally consumed or administered (usuallyself-administered) to the body, by any route of administration, toproduce an effect on the body that the user generally experiences aspleasurable. The substance can be a single substance (cocaine, forexample) or a type of substance (e.g., food, in general). The adverseconsequences can include, for example, adverse effects on health, theability to care for oneself, the ability to form and maintain humanrelationships, and/or the ability to work. The adverse consequences aregenerally significant enough that the user would like to control,reduce, or end substance use or, alternatively, the user's familymembers and/or friends would like to see the user control, reduce, orend substance use. Maladaptive substance use can include uncontrollablecraving for the substance; substance dependence, including psychologicaland/or physical dependence; and maladaptive substance use; as well asany of the individual symptoms of substance dependence and/or abuselisted below.

The term “neurosteroid” refers to a class of steroids, the natural formsof which are produced by cells of the central or peripheral nervoussystems, independently of the steroidogenic activity of the endocrineglands. Neurosteroids are derived from cholesterol, and examples ofneurosteroids include 3α,5α-tetrahydroprogesterone,3α,5β-tetrahydroprogesterone, and 3α,5α-tetrahydrodeoxycorticosterone.For examples, ganaxalone and alphaxalone.

A “benzodiazepine” is referred to an agent selected from the groupconsisting of: alprazolam, chlordiazepoxide, chlordiazepoxidehydrochloride, chlormezanone, clobazam, clonazepam, clorazepatedipotassium, diazepam, droperidol, estazolam, fentanyl citrate,flurazepam hydrochloride, halazepam, lorazepam, midazolam hydrochloride,oxazepam, prazepam, quazepam, temazepam, and triazolam.

A “barbiturate” referred to an agent selected from the group consistingof: amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium,hexobarbital sodium, mephobarbital, metharbital, methohexital sodium,pentobarbital, pentobarbital sodium, phenobarbital, phenobarbitalsodium, secobarbital, secobarbital sodium, talbutal, thiamylal sodium,and thiopental sodium.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present disclosure encompass any composition made by admixing acompound of the present disclosure and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The term “cancer” refers to or describes the physiological condition inmammals that is typically characterized by unregulated cell growth.Examples of cancer include, for example, leukemia, lymphoma, blastoma,carcinoma and sarcoma. More particular examples of such cancers includechronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphiachromosome positive acute lymphoblastic leukemia (Ph+ALL), squamous cellcarcinoma, lung cancer (for examples, small-cell lung cancer, andnon-small cell lung cancer), glioma, gastrointestinal cancer, renalcancer, ovarian cancer, liver cancer (for examples, hepatocellularcarcinoma, fibrolamellar carcinoma, cholangiocarcinoma, angiosarcoma,hepatoblastoma, haemangioma, hepatic adenomas, and focal nodularhyperplasia, and metastasis liver cancer), colorectal cancer,endometrial cancer, kidney cancer, prostate cancer, thyroid cancer,neuroblastoma, pancreatic cancer (for examples, adenocarcinoma, isletcell carcinoma, pancreaticoblastoma, isolated sarcomas and lymphomas,pseudopapillary neoplasms, ampullary cancer, exocrine tumors,neuroendocrine tumors and endocrine tumors), glioblastoma multiforme,cervical cancer, stomach cancer, bladder cancer, hepatoma, breastcancer, colon carcinoma, and head and neck cancer, gastric cancer, germcell tumor, pediatric sarcoma, sinonasal natural killer, multiplemyeloma, metastasis, acute myelogenous leukemia (AML), and chroniclymphocytic leukemia (CML).

It is to be understood that this disclosure is not limited to particularmethods, reagents, compounds, compositions, or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only,and is not intended to be limiting. As used in this specification andthe appended claims, the singular forms “a”, “an”, and “the” includeplural referents unless the content clearly dictates otherwise. Thus,for example, reference to “a compound” includes a combination of two ormore compounds or molecules, and the like.

5.2 Compounds

In one aspect, the present disclosure provides compounds havingstructural Formula (I),

or a salt, solvate, ester, or prodrug thereof;wherein:

A¹ and A² are independently oxygen or sulfur;

R¹ represents NH₂ or R⁷;

R² represents NR⁷ or CR⁷R¹⁰;

R³, R⁵, R⁶, and R⁹ are independently R⁷;

or alternatively, R⁶ and R⁹, taken together with the atom(s) to whichthey are attached, form a 3 to 6 membered optionally substitutedheteroclcylic group containing one or more heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur;

R⁴ represents halogen, CN, NO₂, CF₃, —(CHR)_(n)COOR¹¹, —(CHR)_(n)SO₂R¹¹,C₁₋₄ haloalkyl, —OC₁₋₄-haloalkyl, C₂₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₈ heterocycle,—(CHR)_(n)C₃₋₈ cycloalkyl, —O—C₆₋₁₀ aryl, —O—C₅₋₁₀ heterocycle,—(CHR)_(n)C(O)CF₃, —(CHR)_(n)C(OH)(CF₃)₂, —(CH₂)_(n)halogen, —OR₁₀,—NR¹¹R¹², —NR^(a)COR¹¹, —NR^(a)COOR¹¹, —NR^(a)SO₂R¹¹, —NR^(a)CONR¹¹R¹²,—COR¹¹, tetrazole, —(CHR)_(n)tetrazole, —S—C₁₋₆ alkyl, or —CONR¹¹R¹²,wherein each said alkyl, alkenyl, alkynyl, aryl, cycloalkyl andheterocycle is independently optionally substituted with 1 to 2 groupsof R⁸;

or alternatively, R⁴ and R⁵, taken together with the atom(s) to whichthey are attached, form a 3 to 6 membered optionally substitutedheteroclcylic group containing one or more heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur;

R⁷ and R¹⁰ are independently selected from the group consisting ofhydrogen, halogen, CN, NH₂, NO₂, C₁₋₄ haloalkyl, —OC₁₋₄ haloalkyl, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₈heterocycle, —(CHR)_(n)C₃₋₈ cycloalkyl, —O—C₆₋₁₀ aryl, —O—C₅₋₁₀heterocycle, —C(O)CF₃, —(CH₂)_(n)halogen, —(CHR)_(n)—(O)_(n)—C(═O)R⁸,—(CHR)_(n)—(S)_(n)—C(═O)R⁸, —OR^(a), —NR¹¹R¹², —NR^(a)COR¹¹,—NR^(a)COOR^(a), —NR^(a)SO₂R, —NR^(a)CONR¹¹R¹², —COR^(a),—(CHR)_(n)COOR^(a), —S—C₁₋₆ alkyl, and —CONR¹¹R¹², wherein each saidalkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle isindependently optionally substituted with 1 to 2 groups of R⁸;

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, NR^(a)C(═O)R, halogen, CN, NH₂, NHR^(a), NO₂, C₁₋₄ haloalkyl,—OC₁₋₄ haloalkyl, C₁₋₆ alkyl, C₂₋₈ alkenyl, —S—C₁₋₆ alkyl,—C(═O)—(O)_(n)—R^(a), —(CHR)_(n)—(O)_(n)—C(═O)R⁸,—(CHR)_(n)—(S)_(n)—C(═O)R⁸, —OR^(a), —(CHR)_(n)C₃₋₁₀ cycloalkyl,—(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₁₀ heteroaryl, and —(CHR)_(n)C₅₋₁₀heterocycle, wherein each said alkyl, alkenyl, cycloalkyl, aryl,heteroaryl and heterocycle is independently optionally substituted with1 to 2 groups of R⁸, and wherein one or more carbon atoms of said alkylmay be replaced with one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur;

or alternatively, R¹¹ and R¹², taken together with the atom(s) to whichthey are attached, form a 3 to 6 membered optionally substitutedheteroclcylic group containing one or more heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur; wherein the optionalsubstituent is R⁸; and

R each independently represents hydrogen, halogen, CN, NO₂, NH₂, or C₁₋₆alkyl;

R^(a) each independently represents hydrogen or C₁₋₆ alkyl;

R⁸ each independently represents C₁₋₆ alkyl, halogen, CN, NO₂, NH₂,NHR^(a), SO₂R¹¹, or NR^(a)SO₂R¹¹; and

n represents an integer from 0 to 3, i.e., 0, 1, 2, or 3;

with the following provisos:

when R² is CH₂, R⁴ is not H or CH₃;

when R² is NCH₂CH₂OH, (a) R⁴ is not H or OCH₃, or (b) R⁵ is not OCH₃;and

when R² is N(CH₃), R⁴ is not H, CH₃, OCH₃, or F.

In one embodiment of formula (I), R¹ is selected from the groupconsisting of hydrogen, —(CH₂)_(n)halogen, —CN, —CH₃, NH₂, NHR^(a), and—C₁₋₃ alkyl;

In one embodiment of formula (I), R⁴ is selected from the groupconsisting of —C(O)OR¹¹, —SO₂NHC(═O)CH₃, —C(CF₃)(CF₃)OH, —SO₂NH₂,—C(O)NR¹¹R¹², —CN, —CF₃, —NO₂, —C(O)CF₃, —(CH₂)_(n)halogen,

In one embodiment of formula (I), R³, R⁵, R⁶, and R⁹ are hydrogen.

In one embodiment of formula (I), R² is selected from the groupconsisting of

In one embodiment of formula (I), A¹ and A² are oxygen; R¹ representsNH₂; R² represents NR⁷ or CHR⁷; R³, R⁵, R⁶, and R⁹ are hydrogen; R⁷ isC₅₋₈ heterocycle or C₃₋₈ cycloalkyl; and R⁴ is selected from the groupconsisting of —C(O)OR¹¹, —SO₂NHC(═O)CH₃, —C(CF₃)(CF₃)OH, —SO₂NH₂,—C(O)NR¹¹R¹², —CN, —CF₃, —NO₂, —C(O)CF₃, —(CH₂)_(n)halogen,

In one embodiment of R², it is selected from the group consisting of

In another aspect, the present disclosure provides compounds havingstructural Formula (II):

or a salt, solvate, ester, or prodrug thereof;wherein:

X represents N or CH;

R⁴ represents carboxy bioisostere selected from —(CHR)_(n)COOR¹¹,—(CHR)_(n)SO₂R¹¹, —(CHR)_(n)C₅₋₈ heterocycle, or —(CHR)_(n)C(OH)(CF₃)₂,wherein each said heterocycle is independently optionally substitutedwith 1 to 2 groups of R⁸;

R¹¹ is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, NH₂, NHR^(a), and NR^(a)C(═O)R wherein each said alkyl isindependently optionally substituted with 1 to 2 groups of R⁸, andwherein one carbon atom of said alkyl may be replaced with oneheteroatom selected from the group consisting of nitrogen, oxygen, andsulfur;

R⁸ each independently represents C₁₋₆ alkyl, halogen, CN, NO₂, NH₂,NHR^(a), SO₂R¹¹, or NR^(a)SO₂R₁₁;

R each independently represents hydrogen, halogen, CN, NO₂, NH₂, or C₁₋₆alkyl;

R^(a) each independently represents hydrogen or C₁₋₆ alkyl; and

n represents 0.

In one embodiment of formula (II), X represents N.

In one embodiment of formula (II), R⁴ represents —COOR¹¹, wherein R¹¹ ishydrogen. In one embodiment of formula (II), R⁴ represents —COOR¹¹,wherein R¹¹ is C₁₋₆ alkyl. In some embodiments of formula (II), R⁴represents —COOR¹¹, wherein R¹¹ is C₁₋₆ alkyl where one carbon atom ofsaid C₁₋₆ alkyl is replaced with one nitrogen atom.

In one embodiment of formula (II), X represents N and R⁴ represents—COOR¹¹, wherein R¹¹ is hydrogen.

In another embodiment of formula (II), R⁴ represents —SO₂R¹¹, whereinR¹¹ is NH₂ or NR^(a)C(═O)R. In some embodiments of formula (II), R⁴represents —SO₂R¹¹, wherein R¹¹ is NHC(═O)R and wherein R is C₁₋₆ alkyl.

In one embodiment of formula (II), R⁴ represents C₅ heterocycle, whereinthe heterocycle is a tetrazole.

In certain specific embodiments, the compounds of formula (I) and/orformula (II) are selected from the group consisting of

TABLE 1

(10)

(12)

(14)

(16)

(18)

(20)

(22)

(24)

(26)

(30)

(32)

(34)

(36)

(38)

(40)

Compounds listed in Table 1 may also be represented by their chemicalnames as follows:

ID IUPAC Name

-   10    4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;-   12    4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic    acid;-   14    N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;-   16    1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;-   18    1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;-   20    1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;-   22 methyl    4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;-   24 2-(dimethylamino)ethyl    4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;-   26 ethyl    4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;-   30    4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;-   32    4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic    acid;-   34    N-[(4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;-   36    1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;-   38 2-(dimethylamino)ethyl    4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;    and-   40    1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione.

In one embodiment of the present disclosure, the compounds listed inTable 2 based on Formula (III) are excluded.

TABLE 2 Compound ID X R⁴ R⁵ E1 CH₂ H H E2 CH₂ CH₃ H E3 NCH₃ H H E4 NCH₃CH₃ H E5 NCH₃ F H E6 NCH₃ OCH₃ H E7 NCH₃ H F E8 NCH₃ H OCH₃ E9 NCH₂CH₂OHH H  E10 NCH₂CH₂OH OCH₃ H  E11 NCH₂CH₂OH H OCH₃

5.3 Synthesis of the Compounds

Several methods for preparing the compounds of this disclosure areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following abbreviations are used herein: Me: methyl; Et:ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; BuLi:butyllithium; Piv: pivaloyl; Ac: acetyl; THF: tetrahydrofuran; DMSO:dimethylsulfoxide; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide;Boc: tert-butyloxy carbonyl; Et₃N: triethylamine; DCM: dichloromethane;DCE: dichloroethane; DME: dimethoxyethane; DBA: diethylamine; DAST:diethylaminosulfur trifluoride; EtMgBr: ethylamgnesium bromide; BSA:bovine serum albumin; TFA: trifluoracetic acid; DMF:N,N-dimethylformamide; SOCl₂: thionyl chloride; CDI: carbonyldiimidazole; rt: room temperature; HPLC: high performance liquidchromatography; TLC: thin-layer chromatography. The compounds describedherein may be prepared in a variety of ways known to one skilled in theart.

The procedures described herein for synthesizing compounds the presentdisclosure may include one or more steps of protection and deprotection(e.g., the formation and removal of acetal groups). In addition, thesynthetic procedures disclosed below can include various purifications,such as column chromatography, flash chromatography, thin-layerchromatography (TLC), recrystallization, distillation, high-pressureliquid chromatography (HPLC) and the like. Also, various techniques wellknown in the chemical arts for the identification and quantification ofchemical reaction products, such as proton and carbon-13 nuclearmagnetic resonance (¹H and ¹³C NMR), infrared and ultravioletspectroscopy (IR and UV), X-ray crystallography, elemental analysis(EA), HPLC and mass spectroscopy (MS) can be used as well. Methods ofprotection and deprotection, purification and identification andquantification are well known in the chemical arts.

An Example of Synthetic Scheme for Compounds in Formula (I) and/orFormula (II)

Preparation of Intermediate 2.

30.0 kg of 4-Amino-10-hydroxyanthracen-9(10H)-one (starting material 1)was suspended in MeOH (70 L). To the suspension, 53.7 kg of bromine wasadded to the suspension at 60° C. about 1 hr. After the addition ofbromine, the reaction mixture was stirred at 50-60° C. for about 18-24hours. The reaction mixture was then cooled. The resulting suspensionwas filtered, washed with MTBE. The red solid was dried to giveIntermediate 2 as a red solid (˜50.0 kg, yield 98%). HPLC analysisshowed 96% purity. ¹H-NMR (CDCl₃, 300 Hz) δ 8.26 (m, 2H), 8.09 (s, 1H),7.80 (m, 2H).

Preparation of Intermediate 3a.

2.99 kg of NaNO₂ was added to cooled H₂SO₄ (27.8 L) solution gently. Themixture was stirred at 35° C. for 1 hr. Intermediate 2 (15.0 kg) wasthen added to the mixture and stirred at 50-55° C. for 4 h. After cooledto room temperature, the reaction mixture was poured into crushed ice.The yellow solid was precipitated out. The solid was collected byfiltration, washed with ice-water, followed by 1:1 mixture ofethanol/MTBE to give a wet solid, which was dried. 24.7 kg of the crudedamp product was obtained. The product was used for the next stepwithout further purification.

Preparation of Intermediate 3.

A 100 L jacketed reactor was charged with the solution of NaN₃ (2.73 kg)in water. Intermediate 3a was added at room temperature, and the mixturewas stirred at room temperature overnight. An aqueous solution of NaOH(6N) was then added slowly to the mixture. Then the solid was collectedby filtration and washed with water. The filtrate cake was slurred withwater, filtered, and washed with water, and followed by the mixture ofacetone/water (9:1), air dried to give crude Intermediate 3 (23.2 kg ofdamp solid). HPLC analysis showed 95% purity. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.51 (s, 1H), 8.11-8.15 (m, 2H), 7.91-7.94 (m, 2H).

Preparation of Intermediate 4.

26.5 kg of crude Intermediate 3 was added to toluene at about 50-70° C.The mixture was then stirred at 50-70° C. overnight. After the reactiontemperature was cooled to RT, the solid product was collected. Thefilter cake was washed with MeOH. The solid obtained was re-suspended inMeOH and stirred at room temperature for about 1-3 hour. Afterfiltration, 13.3 kg of the wet product of Intermediate 4 was obtained asa yellow solid. HPLC analysis showed 98.7% purity. ¹H-NMR (300 MHz,DMSO-d₆): δ 8.27 (m, 2H), 8.13 (m, 1H), 7.91 (m, 1H), 7.78 (m, 1H).

Preparation of Intermediate 5.

Mixing 4-amino benzoic acid and lithium hydroxide in DMAc, then adding3,5-dibromo-6H-anthra[1,9-cd]isoxazol-6-one into the mixture at about40-60° C. Stirring the reaction mixture for up to 24 hours. Adding MTBEto the reaction mixture. Filtering the solid and drying to get4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid(Intermediate 5).

Preparation of Intermediate 6.

Dissolving Intermediate 5 in DMSO, then adding triethylamine and1-cyclohexyl piperazine into the solution at temperature about 50-70° C.Adding MTBE and MeOH solution. Isolation and washing of the wet cakewith MTBE and MeOH followed by filtering provided Intermediate 6 as asolid.

Preparation of Compound 12.

In a flask, Intermediate 6, Pd/C and hydrazine were mixed and heated forabout 4 hours. Reaction mixture was cooled to room temperature andfiltered, and then it was redissolved in TFA/DMAc and active charcoal,and then filtered through celite. NaHCO₃ was added to neutralize themixture and the solid was collected by filtration. Compound 12 waspurified and dried. It gave about 99% (HPLC, area %) purity. Massspectra gave [M+1]=525.5. ¹H-NMR (300 MHz, DMSO-d6), ppm (δ): 12.36 (1H,s), 8.27 (2H, d), 7.95 (2H, d), 7.85 (2H, t), 7.42 (2H, d), 7.25 (1H,s), 2.96 (4H, m), 2.74 (4H, m), 2.27 (2H, m), 1.57-1.80 (6H, m),1.06-1.23 (5H, m).

5.3 Biological Activities

Compound Inhibition in a Radiometric Based Mixed Micelle Assay:

In a final reaction volume of 25 μL, TrkA (h) (3 nM) is incubated withthe kinase reaction buffer (20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mMEGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO),0.2 mg/ml substrate PolyEY(4:1) and 2 nM MnCl₂, and [³³P-ATP](specificactivity approx. 500 cpm/pmol, concentration as required). The reactionis initiated by the addition of the MgATP mix. After incubation for atleast 40 minutes at room temperature, the reaction is stopped by theaddition of 5 μL of a 3% phosphoric acid solution. 10 μL of the reactionis then spotted onto a P30 filtermat and washed three times for 5minutes in 75 mM phosphoric acid and once in methanol prior to dryingand scintillation counting. TrkA: Recombinant Human Cytoplasmic Domain(amino acids 441-796), Histidine-tagged, expressed in insect cells.Activated in vitro via auto-phosphorylation. Mw=42.8 kDa. Substrates forkinases: poly(EY) for TRKA; poly(EY)(4:1) with 2 mM MnCl₂, average Mw=16kDa Standard conditions (unless otherwise specified): 30 nM TRKA, 0.2mg/ml poly(EY)+2 mM MnCl₂, and 10 μM ([γ-³³P]) ATP. Using the similarassay condition with other kinases of recombinant human cytoplasmicdomain, the activities of other kinases could be also measured.

The TrkA kinase antagonist activity of a compound which may be used inthe present disclosure may be determined by these assays. In particular,the compounds of the present disclosure aforementioned examples,including Table 1 had activity in antagonizing the TrkA kinase activityin the aforementioned assays, generally with an IC50 of less than about25 μM. Preferred compounds within the present disclosure had activity inantagonizing the TrkA kinase activity in the aforementioned assays withan IC50 of less than about 2.5 μM. Further preferred compounds withinthe present disclosure had activity in antagonizing the TrkA kinaseactivity in the aforementioned assays with an IC50 of less than about0.25 μM. The much further preferred compounds within the presentdisclosure had activity in antagonizing the TrkA kinase activity in theaforementioned assays with an IC50 of less than about 0.1 μM. Forexamples, Compound A of the present disclosure has an IC50 of 0.085 μM;Compound 12 of the present disclosure has about 99.6% inhibition of TrkAkinase at 10 μM concentration or an IC50 of about 50 to 150 nM and hasmore than about 10 μM of the IC50 values antagonizing, for instances,the following structurally related protein kinases and other more than400 kinases, including TrkB, TrkC, ABL1, AKT1, ALK5/TGFB-R1, ARAF, AXL,BMX, BTK, CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, c-MET, c-Src, EPHA1,FES/FPS, FGFR1, FGR, FLT1, FLT3 (CD), FMS, FYN, IGF-1R, IR, ITK, JAK3,JNK3, LCK, LYN, MEK1, MEK2, MLK1/MAP3K9, MUSK, P38a/MAPK14, P38b/MAPK11,PDGFRa, PDGFRb, PKA, PKCalpha, PKCbetaI, PKCbetaII, PKCdelta,PKCepsilon, PKCeta, PKCgamma, PKCiota, PKCmu/PKD1, PKCtheta, PKCzeta,PKD2/PRKD2, PKG1a, PKG1b, RAF1, RET, TEC, TGFbR2, TIE2/TEK, VEGFR2/KDR,VEGFR3/FLT4 (duplicate, with a positive control compound of a pan-kinaseinhibitor, staurosporine or K-252a). Such a result is indicative of theintrinsic activity of the compounds in use as isoform-selectiveantagonists of TrkA kinase activity.

Compound Inhibition in a Live, Whole Cell Based Functional Assay:

There are several methods to measure whole length TrkA activationstimulated by its natural ligand or agonist NGF in live cells. Forexample, the PathHunter Profiling services offered by DiscoveRx(Fremont, Calif.). The PathHunter technology is an adaptation of enzymefragment complementation that provides a novel, generic functionalcell-based assay format for detecting protein-protein interactions. Inthis cell-based assay approach, with U2OS cell background, a smallpeptide epitope (PK) is expressed recombinantly on the intracellularC-terminus of TrkA (human full length). This is co-expressed with alarger sequence, termed enzyme acceptor (EA) that is attached to acytoplasmic protein SHC1 which will interact with TrkA intracellularly.NGF induced activation of TrkA receptor causes either homo- orhetero-dimerization of TrkA resulting in cross-phosphorylation. TheSHC1-EA fusion protein then binds the phosphorylated TrkA receptorforcing complementation of the PK and EA fragment. This interactiongenerates an active beta-galactosidase enzyme, which is detected using achemiluminescent substrate.

In such cell-based functional assays, for example, Compound 12 of thepresent disclosure inhibits NGF stimulated TrkA activation at lownanomolar concentration (cellular IC₅₀ is about 50-150 nM), whilevirtually has no effect on either BDNF stimulated TrkB, or NT3stimulated TrkC activation (IC₅₀>10 μM in both cases, triplicate, with apositive control compound of pan-kinase inhibitor, staurosporine orK-252a, an internal agonist control and a negative control compound).

Mode of Inhibition with Respect to ATP.

The TrkA kinase assays were performed at room temperature. Fourconcentrations of compounds (0, 0.037, 0.11, and 0.33 μM) were addedinto Enzyme/substrate mixture using acoustic technology, and incubatedfor 40 min to ensure all compounds were equilibrated and bound to theenzyme. Then various concentrations of ATP (10, 100, 200, 350, and 500μM ATP with 0.2 mg/ml poly(EY)) were added to initiate the reaction. Theactivity was monitored every 5-15 min for time course. Such kineticanalysis shows that Compound D, for example, inhibits TrkAnon-competitively with respect to ATP: Lineweaver-Burk double-reciprocalplots showing differences in Vmax but not in km for the 4 conditions.

Mode of Inhibition with Respect to Substrate.

The kinase assays were performed similar manner to ATP study. Variousconcentrations of compounds (0, 0.037, 0.11, and 0.33 μM) were addedinto Enzyme/substrate mixture using acoustic technology, and incubatedfor 40 min to ensure all compounds were equilibrated and bound to theenzyme. Then 10 μM ATP and various concentrations of substrate (0.02,0.05, 0.1, 0.2, and 0.5 mg/ml poly(EY)) were added to initiate thereaction. The activity was monitored every 5-15 min for time course.Such kinetic analysis shows that Compound D, for example, inhibits TrkAnon-competitively with respect to substrate: Lineweaver-Burkdouble-reciprocal plots showing differences in Vmax but not in km forthe 4 conditions.

Cell Viability and Proliferation Assays.

To assess the chemosensitivity of tumor cells, cell viability ismeasured by CellTiter-Glo® Luminescent Cell Viability Assay (Promega;WI, USA) per the manufacturer's instruction. Briefly, 5×10³ to 7×10⁵cells/ml are cultured in sterile 96-well plates in the presence ofincreasing concentrations of the drugs (test article, 0 to 100 μM), orvehicle in RPMI medium. The plates are then incubated for 24 to 96 h,and then 100 μl of CellTiter-Glo reagent is added to lyse the cells.After a 10-min incubation at room temperature, the luminescence isrecorded in a luminometer with an integration time of 1 s per well. Theluminescence signals for the drug-treated cells are normalized by theluminescence signal obtained from vehicle-treated cells. As analternative method to quantitate cell viability, the trypan blueexclusion dye method was used. Vehicle- or drug-treated cells wereassayed by adding trypan blue solution (0.4% in phosphate-bufferedsaline [PBS]) to the culture medium. After 3 min, the number of deadcells that retained the dye is compared to the total number of cells tocalculate cell viability. GraphPad Prism 5 software is used to calculateIC50 and plot effect-dose curve of drugs. Multiplate reader: EnVision2104 (PerkinElmer). % of controlvariability=100*[(X(drug_treated)−L(baseline))/(H(vehicle_control)−L(baseline))].Such assays show that for example, Compound 12, has IC50 values about 2to 5 μM in human pancreatic cancer cells (from ATCC) of AsPC-1, MIAPaCa-2, BxPC-3, Capan-1 and Panc-1; about 5 μM in human liver cancercells of SK-HEP-1 and HepG2; and about 7 μM in human stomach cancercells of NCI-N87, after 24 incubation. Taxol, erlotinib, sorafenib andgemcitabine are used as controls, and the compounds of presentdisclosures are synergistic or additive with gemcitabine in pancreaticcancer cells or are synergistic or additive with sorafenib in livercancer cells.

Pharmacokinetic and Bioavailabilities after Oral and Intraperitoneal(i.p.) Treatment Bioavailability in CD-1 Mice.

Pharmacokinetics and bioavailability of after oral and i.p. treatment inCD-1 mice (n=4 per dose group) are determined. For example, for Compound12, the oral bioavailability in CD-1 mice is about 100% after 50 mg/kgoral dosing of the drug; i.p. bioavailability is about 100% after 50mg/kg i.p. dosing of the drug; the elimination half-life is about 1 hafter intravenous dosing and about 3.5 h after i.p. dosing and about 4.5h after oral dosing, of the Compound 12.

Chronic Constriction Injury (CCI) Model of Neuropathic Pain in Rats.

The CCI model is one of the most commonly used mono-neuropathic painmodel firstly described in details by Bennett and Xie (Bennett G J, XieY K. Pain. 1988; 33(1):87-107). It mimics important clinical chronicpain symptoms such as mechanical allodynia and thermal hyperalgesia.Chronic constriction injury of the sciatic nerve was produced by tyingfour loose ligatures around the left sciatic nerve according to themethod of Bennett and Xie. This procedure resulted in tactile allodyniain the left hindpaw. Calibrated von Frey filaments were used todetermine the lowest mechanical (tactile) threshold required to evoke abrisk paw withdrawal reflex in the rat hindpaws. Rats were allowed toacclimatize in wire mesh cages for 15-20 min prior to von Frey testing.Assessment of paw withdrawal thresholds (PWTs) using von Frey filamentswas undertaken prior to CCI-surgery (pre-surgery baseline on day 0).Before the drug dosing on day 14, the pre-dose baseline was recorded foreach rat. Rats were included in the study only if they did not exhibitmotor dysfunction (e.g., paw dragging or dropping) and their PWT wasbelow to 4 g. Drug-naïve CCI-rats (n=4-6 per group) were used. The oralvehicle was 0.5% CMC-Na/0.1% Tween 80 in distilled water. The positivecontrol gabapentin was dissolved in the vehicle and orally given at 100mg/kg (by oral gavage). Test compound was suspended in the vehicle andorally given at 50 mg/kg and 100 mg/kg. Each CCI-rat was administered asingle oral dose of test compound, gabapentin or vehicle control, 2hours before assessment of PWT. In such rat neuropathic pain model that,for example, Compound 12, has shown about 48% relative analgesic effectat 150 mg/kg oral dose compared to analgesic effect produced by morphine(HCl) at 3 mg/kg, s.c.

The results have demonstrated that oral administration of, for example,Compound D of present disclosure significantly reduced mechanicalallodynia in CCI rats of neuropathic pain model in a dose-dependentmanner. In addition, at the same oral dose of 100 mg/kg, Compound D isabout 98% more effective in suppressing mechanical allodynia in CCIneuropathic pain compared to gabapentin, the current gold standardmedication for neuropathic pain, while even 50 mg/kg oral Compound D isabout 28% more effective than 100 mg/kg oral gabapentin. Of note,CCI-rats dosed with gabapentin have shown drowsiness or motorincoordination, which is consistent with known side effect ofgabapentin. However, no such effect or other abnormality was observed inCCI-rats dosed with Compound D.

Furthermore, there is no statistically significant difference ofanti-allodynia effects as measured on day 14 and on day 20 for the samegroup of CCI-rats treated with the same single oral dose of Compound Dat 100 mg/kg, indicating that there is no tolerance issue.

Spinal Nerve Ligation (SNL) Mono-Neuropathic Pain Model in Rats.

The surgical procedure will be performed according to the method firstlydescribed by Kim and Chung (Kim S H, Chung J M. Pain. 1992;50(3):355-63). This procedure will result in tactile allodynia in theleft hindpaw. Rats will be included in the study only if they do notexhibit motor dysfunction (e.g., paw dragging or dropping) and their PWTis below to 4.0 g.

The Dose-Response Anti-Allodynia Effects of Test Compound:

On day 14 after surgery, rats will be treated with test compound at oneof four doses, vehicle or positive control by oral gavage, and PWT isdetermined by calibrated von Frey filaments at time points of 0 (rightbefore the drug dosing, Pre-Dose Baseline), 0.5, 1, 2, 4 and 6 hr.

Tolerance Effects:

6 days following the day 14 test, i.e. on day 20 after surgery, the sameprocedure on day 14 will be repeated on day 20 with the same group ofCCI-rats treated with the same (effective) dose as on day 14. Theresults of anti-allodynia effects of test compound as tested on day 14and on day 20 will be compared to see if there is any tolerance effectof test compound in animals.

The Anti-Allodynia Effects of Repeated Administration of Test Compound:

Administration of test compound will start on day 7 after surgery, oncea day for 7 days. PWT will be determined by calibrated von Freyfilaments once a day, 2 hour after compound dosing. After 7 days dosing,the measurement will be continued, every other day without compounddosing for another 7 days. PWT will be determined at the time points asgiven above.

Thermal Hyperalesia Effects.

Thermal hyperalgesia may be assessed in the SNL rats by plantar testwith a single dose of TEST COMPOUND at the time points given above.

Streptozotocin-Induced Diabetic Poly-Neuropathic Pain Model.

Diabetic peripheral neuropathy is a long-term complication of diabetesmellitus. Rats will receive i.p. injections of streptozotocin (STZ, 50mg/kg dissolved in citrate buffer at pH 4.5 immediately before theinjection) to induce insulin-dependent diabetes mellitus and producetactile allodynia. One week later, blood glucose level will be assayed,from samples taken from the tail vein, using standard test strips andcolorimeter. Only animals with a blood glucose level >350 mg/dL will beconsidered diabetic and included for the testing. Typical features ofneuropathic pain (tactile allodynia) will be developed in hindpawsbeginning around 2 to 3 weeks after STZ injection. After 4 weeks, astable level of allodynia will be usually reached. At this point, therats with PWT below 4.5 g will be enrolled for compound testing. Theallodynic state will remain intact until the 8^(th) week after STZinjection. All animals will be observed daily and weighed regularlyduring the study period. This model of neuropathic pain mimics thesymptoms of neuropathy in diabetic patients (Lynch J J, 3rd, et al Eur JPharmacol. 1999; 364(2-3):141-6; Calcutt N A, J Neurol Sci. 2004;220(1-2):137-9).

The Dose-Response Anti-Allodynia Effects of Test Compound:

On day 28 after STZ injection, rats will be treated with test compoundat one of four doses, or controls (vehicle and positive) by oral gavage,and PWT will be determined by calibrated von Frey filaments at timepoints of 0 (right before the drug dosing, Pre-Dose Baseline), 0.5, 1,2, 4 and 6 hr.

Tolerance Effects:

6 days following the day 28 test, i.e. on day 34 after STZ injection,the same procedure on day 28 will be repeated on day 34 with the samegroup of STZ-rats treated with the same (effective) dose as on day 28.The two results of anti-allodynia effects of test compound as measuredon day 28 and on day 34 will be compared to see if there is anytolerance effect of test compound in animals.

The Anti-Allodynia Effects of Repeated Administration of Test Compound:

Administration (p.o.) of test compound will start on day 21 after STZinjection, once a day for 7 days. PWT will be determined by calibratedvon Frey filaments once a day, 1 hour after compound dosing. After 7days dosing, the measurement will be continued, every other day withoutcompound dosing for another 7 days. PWT is determined at the time pointsas given above. The thermal hyperalgesia assessment by plantar test maybe performed in STZ models with a single dose and PWL will bedetermined, at time points as given above.

Carrageenan Pain Model

The carrageenan model is a fast, reliable model used to assess theability of analgesics to block inflammatory pain. The analgesic effectsof test article combinations on pain generation are assayed using thecarrageenan-induced pain model in rats. Adult male Sprague-Dawley ratsare administered study drugs orally (vehicle, compounds of presentdisclosure) once daily for 2 days (day −2 and day −1) and 30 minutesprior to the carrageenan injection on day 0 (time=0). For thecarrageenan injection, animals are lightly anesthetized and 0.1 ml of 2%carrageenan is injected into the plantar surface of the right hind paw.The positive control indomethacin (30 mg/kg, p.o.) is administeredorally immediately before the carrageenan injection. Paw volumes (rightand left) are measured using a Plethysmometer before drug administrationon day −2 and serve as a baseline measurement. The paw volumes aremeasured again two hours post carrageenan injection. The degree ofmechanical allodynia is measured by a blinded observer using Von Freyfilaments applied to the plantar surface of the hind paws in anincreasing numerical order. Each filament increases the force applied onthe paw. The filaments are applied until animal paw withdrawal isachieved. This procedure is carried out before drug administration (day−2), on day −1 and on day 0 at time=0, 20, 40, 60, 80 and 120 minutespost-carrageenan. The force (expressed in grams) required for pawwithdrawal after carrageenan injection is subtracted from the forcerequired for paw withdrawal before carrageenan injection. Results areexpressed as mean change from baseline across five timepoints postcarrageenan injection. In such rat pain model that, for example,Compound 12, has shown about 85% relative analgesic effect at 150 mg/kgoral dose compared to analgesic effect, about 100% produced byindomethacin (30 mg/kg, p.o.).

In Vivo Evaluation of Anti-Tumor Efficacy of a Compound of Formula (I)and/or Formula (II) in PANC-1 Subcutaneous Human Pancreatic CancerXenograft Mouse Model.

In vivo therapeutic efficacy of a Compound of Formula (I) and/or Formula(II) (test article) and its combination with gemcitabine in PANC-1subcutaneous human pancreatic cancer xenografts in BALB/c female nudemice (with body weight ranged 18-23 grams) was performed.

Animal Housing:

Animals were kept in laminar flow rooms at constant temperature andhumidity with 4 or 3 animals in each cage. Temperature: 22±3° C.Humidity: 50±20%. Light cycle: 12 hours light and 12 hours dark. Cages:Polycarbonate cages of 300 mm×180 mm×150 mm embedded with the soft woodmaterial were used. The bedding was changed twice a week. Diet: Animalshad free access to a certified commercial laboratory diet.Concentrations of contaminants in the diet are routinely analyzed by themanufacturers to ensure the contaminants are below their allowablemaximum and thus would not affect the tumor growth.

Water:

Animals had free access to sterile drinking water. Cage identification:The identification labels for each cage contained the followinginformation: number of animals, sex, strain, date received, treatment,group number and the starting date of the treatment. Briefly, PANC-1cell line was originally purchased from the ATCC (CRL-1469) and thePANC-1 primary cell line was derived from the PANC-1 subcutaneouslyxenograft tumors. The PANC-1 primary cells were maintained in vitro asmonolayer culture in DMEM medium supplemented with 10% heat inactivatedfetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin andL-glutamine (2 mM) at 37° C. in an atmosphere of 5% CO₂ air. The cellsgrowing in exponential phase were harvested and counted for tumorinoculation.

Tumor Cell Inoculation and Randomization:

Each animal was inoculated subcutaneously on the right flank with thePANC-1 primary tumor cells (5×10⁶/animal) in 0.1 mL of PBS. Tumordevelopment was allowed undisrupted until mean tumor volume reachedapproximately 85 mm³. Animals were then randomized into 6 groups, witheach group consisting of 8 animals. The test articles were administeredto the tumor-bearing animals according to predetermined regimens. Allthe procedures related to animal handling, care and the treatment inthis study were performed according to guidelines approved by theInstitutional Animal Care and Use Committee (IACUC) of the testing labfollowing the guidance of the Association for Assessment andAccreditation of Laboratory Animal Care (AAALAC). At the time of routinemonitoring, the animals were checked for any effects of tumor growth onnormal behavior such as mobility, food and water consumption (by lookingonly), body weight (BW) gain/loss (BW was measured twice weekly),eye/hair matting and any other abnormal effect. Death and observedclinical signs were recorded on the basis of the numbers of animalswithin each subset.

Tumor Measurement and the Endpoints:

The major endpoint was to evaluate if the tumor growth could beinhibited. Tumor measurement was conducted twice weekly with a caliperand the tumor volume (mm3) is estimated using the formula: TV=a×b²/2,where a and b are long and short diameters of a tumor, respectively. Thetumor sizes were then used for T/C value and TGI (tumor growthinhibition), which are indicators of anti-tumor effectiveness. The T/Cvalue (in percent) is an indication of antitumor effect. T and C are themean volumes of the treated and control groups, respectively, on a givenday. BW change, expressed as %, is calculated using the followingformula: BW change (%)=(BW_DayX/BW_Day0)×100, where BW_DayX is BW on agiven day, and BW_Day0 was BW on Day 0 (tumor inoculation).

Tumor Sample Collection:

Two tumor samples from Group 1, 2 and 3, respectively; six tumor samplesfrom Group 4; five tumor samples from Group 5 and 6, respectively, weresnap frozen in liquid nitrogen and kept at −80° C. Total 22 tumorsamples were collected.

Statistical Analyses:

A one-way ANOVA was performed to compare tumor volumes among groups. Alldata were analyzed using the SPSS 17.0 software; p<0.05 was consideredstatistically significant. The in vivo anti-tumor efficacy of Compound12, either alone or in combination with gemcitabine are listed infollowing two tables.

The results indicated that the Compound 12 was efficacious in reducingtumor growth, either alone or in combination with the current standardcare medicine, gemcitabine and, the combination of Compound 12 andgemcitabine showed great synergistic efforts and, having greater tumorreduction than either Compound 12 or gemcitabine alone.

Mean Tumor Volumes of Different Groups

Tumor volume (mm³)^(a) Gemcitabine Gemcitabine Gemcitabine GemcitabineCompound- 10 mg/kg + 20 mg/kg + Days Vehicle 10 mg/kg 20 mg/kg 12Compound-12 Compound-12 7 84 ± 5 83 ± 4 83 ± 3 84 ± 4 85 ± 5 82 ± 4 11149 ± 11 142 ± 12 109 ± 8  111 ± 5  90 ± 6 89 ± 6 14 193 ± 15 174 ± 9 138 ± 9  157 ± 15 128 ± 12 115 ± 7  18 357 ± 25 346 ± 21 184 ± 13 234 ±8  138 ± 8  127 ± 10 19 402 ± 27 374 ± 19 216 ± 18 276 ± 27 150 ± 10 143± 7  Note: ^(a)Mean ± SEMAntitumor Activity of Compound-12 and its Combination with Gemcitabinein Treatment of Subcutaneous PANC-1 Human Pancreatic Cancer XenograftModel

Tumor Volume TGI (%, Treatment (mm³, D18)^(a) P value^(b) D18) G1:Vehicle 357 ± 25 — — G2: Gemcitabine 10 mg/kg 346 ± 21 1.000 3 G3:Gemcitabine 20 mg/kg 184 ± 13 0.001 48 G4: Compound-12 234 ± 8  0.018 34G5: Gemcitabine 10 mg/kg + 138 ± 8  <0.001 61 Compound-12 G6:Gemcitabine 20 mg/kg + 127 ± 10 <0.001 64 Compound-12 Note: ^(a)Mean ±SEM; ^(b) vs. control. P values: G2 vs. G3 < 0.001; G2 vs. G4 = 0.008;G2 vs. G5 < 0.001; G2 vs. G6 < 0.004; G3 vs. G4 = 0.094; G3 vs. G5 =0.134; G3 vs. G6 = 0.062; G4 vs. G5 < 0.001; G4 vs. G6 < 0.001; G5 vs.G6 = 0.998

5.4 Therapeutic Uses

In accordance with the present disclosure, a compound of the presentdisclosure, or a salt, solvate, ester, and/or a prodrug thereof, or apharmaceutical composition containing the compound, or a salt, solvate,ester, and/or a prodrug thereof, is administered to a patient,preferably a human, suffering from a variety of disorders. These includecancers, anxiety, generalized pain disorder, acute pain, chronic pain,inflammatory pain and neuropathic pain.

While the disclosure has been described and illustrated with referenceto certain preferred embodiments, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of thedisclosure.

5.5 Therapeutic/Prophylactic Administration

The present compounds, or salts, solvates, esters, and/or prodrugsthereof, or pharmaceutical compositions containing the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, may beadvantageously used in human medicine. As previously described inSection 6.4 above, the present compounds are useful for the treatment orprevention of various diseases.

When used to treat or prevent the above-mentioned diseases or disorders,the present compounds may be administered or applied solely, or incombination with other active agents (e.g., other pain agents).

The present disclosure provides methods of treatment and prophylaxis byadministration to a patient in need of such treatment a therapeuticallyeffective amount of one or more compounds of the present disclosure, orsalts, solvates, esters, and/or prodrugs thereof. The patient may be ananimal, more preferably, a mammal and most preferably, a human.

The present compounds, or salts, solvates, esters, and/or prodrugsthereof, may be administered orally. The present compounds, or salts,solvates, esters, and/or prodrugs thereof, may also be administered byany other convenient route, for example, by infusion or bolus injection,by absorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.). Administration can besystemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer a compound and/or pharmaceuticalcomposition thereof. Methods of administration include, but are notlimited to, intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intranasal,intracerebral, intravaginal, transdermal, rectally, by inhalation, ortopically, particularly to the ears, nose, eyes, or skin. The preferredmode of administration is left to the discretion of the practitioner andwill depend in-part upon the site of the medical condition. In mostinstances, administration will result in the release of the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, into thebloodstream of a patient.

In specific embodiments, it may be desirable to administer one or moreof the present compounds, or salts, solvates, esters, and/or prodrugsthereof, locally to the area in need of treatment. This may be achieved,for example, and not by way of limitation, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. In some embodiments, administration canbe accomplished by direct injection at the site (or former site) ofcancer or arthritis.

In certain embodiments, it may be desirable to introduce one or more thepresent compounds, or salts, solvates, esters, and/or prodrugs thereof,into the central nervous system of a patient by any suitable route,including intraventricular, intrathecal and epidural injection.Intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

The present compounds, or salts, solvates, esters, and/or prodrugsthereof, may also be administered directly to the lung by inhalation.For administration by inhalation, the present compounds, or salts,solvates, esters, and/or prodrugs thereof, may be conveniently deliveredto the lung by a number of different devices. For example, a MeteredDose Inhaler (“MDI”), which utilizes canisters that contain a suitablelow boiling propellant, (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or anyother suitable gas), may be used to deliver compounds of the disclosuredirectly to the lung.

Alternatively, a Dry Powder Inhaler (“DPI”) device may be used toadminister the present compounds, or salts, solvates, esters, and/orprodrugs thereof, to the lung. DPI devices typically use a mechanismsuch as a burst of gas to create a cloud of dry powder inside acontainer, which may then be inhaled by the patient. DPI devices arealso well known in the art. A popular variation is the multiple dose DPI(“MDDPI”) system, which allows for the delivery of more than onetherapeutic dose. For example, capsules and cartridges of gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the disclosure and a suitable powder base such aslactose or starch for these systems.

Another type of device that may be used to deliver the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, to thelung is a liquid spray device supplied, for example, by AradigmCorporation, Hayward, Calif. Liquid spray systems use extremely smallnozzle holes to aerosolize liquid drug formulations that may then bedirectly inhaled into the lung.

In some embodiments, a nebulizer is used to deliver the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, to thelung. Nebulizers create aerosols from liquid drug formulations by using,for example, ultrasonic energy to form fine particles that may bereadily inhaled (see e.g., Verschoyle et al., British J. Cancer, 1999,80, Suppl. 2, 96. Nebulizers are available from a number of commercialsources such as Sheffield/Systemic Pulmonary Delivery Ltd. Aventis andBatelle Pulmonary Therapeutics.

In other embodiments, an electrohydrodynamic (“EHD”) aerosol device isused to deliver the present compounds, or salts, solvates, esters,and/or prodrugs thereof, to the lung. EHD aerosol devices use electricalenergy to aerosolize liquid drug solutions or suspensions (see e.g.,Noakes et al., U.S. Pat. No. 4,765,539). The electrochemical propertiesof the formulation may be important parameters to optimize whendelivering the present compounds, or salts, solvates, esters, and/orprodrugs thereof, to the lung with an EHD aerosol device and suchoptimization is routinely performed by one of skill in the art. EHDaerosol devices may more efficiently deliver drugs to the lung thanexisting pulmonary delivery technologies.

In other embodiments, the present compounds, or salts, solvates, esters,and/or prodrugs thereof, can be delivered in a vesicle, in particular aliposome (See, Langer, 1990, Science, 249:1527-1533; Treat et al., in“Liposomes in the Therapy of Infectious Disease and Cancer,”Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989);see generally “Liposomes in the Therapy of Infectious Disease andCancer,” Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365(1989)).

In other embodiments, the present compounds, or salts, solvates, esters,and/or prodrugs thereof, can be delivered via sustained release systems.In still other embodiments, the sustained release system is an oralsustained release systems. In still other embodiments, a pump may beused (See, Langer, supra; Sefton, 1987, CRC Crit Ref Biomed Eng. 14:201;Saudek et al., 1989, N. Engl. J Med. 321:574).

In still other embodiments, polymeric materials can be used in thepharmaceutical compositions containing the present compounds, or salts,solvates, esters, and/or prodrugs thereof. (for exemplary polymericmaterials, see “Medical Applications of Controlled Release,” Langer andWise (eds.), CRC Pres., Boca Raton, Fla. (1974); “Controlled DrugBioavailability,” Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol.Sci. Rev. Macromol Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J.Neurosurg. 71:105). In still other embodiments, polymeric materials areused for sustained release delivery of oral pharmaceutical compositions.Exemplary polymers include, but are not limited to, sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropyl methylcellulose). Other cellulose ethers have beendescribed (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9).Factors affecting drug release are well known to the skilled artisan andhave been described in the art (Bamba et al., Int. J. Pharm., 1979, 2,307).

In other embodiments, enteric-coated preparations can be used for oralsustained release administration. Coating materials include, but are notlimited to, polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

In still other embodiments, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In still other embodiments, OROS™ osmotic devices areused for oral sustained release delivery devices (Theeuwes et al., U.S.Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

In still other embodiments, a controlled-release system can be placed inproximity of the target of the present compounds, or salts, solvates,esters, and/or prodrugs thereof, thus requiring only a fraction of thesystemic dose (See, e.g., Goodson, in “Medical Applications ofControlled Release,” supra, vol. 2, pp. 115-138 (1984)). Othercontrolled-release systems discussed in Langer, 1990, Science249:1527-1533 may also be used.

5.6 Pharmaceutical Compositions of the Disclosure

In one aspect, the present disclosure provides pharmaceuticalcompositions comprising one or more compounds of the present disclosureincluding the compound having structural formula (I) and/or formula (II)and any of their subgeneric groups and specific embodiments describedabove in Section 5.2.

The present pharmaceutical compositions contain a therapeuticallyeffective amount of one or more compounds of the present disclosure, orsalts, solvates, esters, and/or prodrugs thereof, preferably in purifiedform, together with a suitable amount of a pharmaceutically acceptablevehicle, so as to provide a form for proper administration to a patient.When administered to a patient, the present compounds and thepharmaceutically acceptable vehicles are preferably sterile. Water is apreferred vehicle when a compound is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid vehicles, particularly for injectable solutions.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present pharmaceutical compositions, if desired, can alsocontain minor amounts of wetting or emulsifying agents, or pH bufferingagents. In addition, auxiliary, stabilizing, thickening, lubricating andcoloring agents may be used.

Pharmaceutical compositions may be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the disclosureinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In some embodiments, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other examples of suitable pharmaceutical vehicles havebeen described in the art (see Remington: The Science and Practice ofPharmacy, Philadelphia College of Pharmacy and Science, 20^(th) Edition,2000).

For topical administration a compound may be formulated as solutions,gels, ointments, creams, suspensions, etc. as is well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration. Systemic formulationsmay be made in combination with a further active agent such as anotheranti-cancer agent.

In some embodiments, the present compounds, or salts, solvates, esters,and/or prodrugs thereof, are formulated in accordance with routineprocedures as a pharmaceutical composition adapted for intravenousadministration to human beings. Typically, compounds for intravenousadministration are solutions in sterile isotonic aqueous buffer. Forinjection, the present compounds, or salts, solvates, esters, and/orprodrugs thereof, may be formulated in aqueous solutions, preferably, inphysiologically compatible buffers such as Hanks' solution, Ringer'ssolution, or physiological saline buffer. The solution may containformulatory agents such as suspending, stabilizing and/or dispersingagents. When necessary, the pharmaceutical compositions may also includea solubilizing agent. Pharmaceutical compositions for intravenousadministration may optionally include a local anesthetic such aslignocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. When the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, areadministered by infusion, it can be dispensed, for example, with aninfusion bottle containing sterile pharmaceutical grade water or saline.When the present compounds, or salts, solvates, esters, and/or prodrugsthereof, are administered by injection, an ampoule of sterile water forinjection or saline can be provided so that the ingredients may be mixedprior to administration.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered pharmaceutical compositions may contain one or moreoptional agents, for example, sweetening agents such as fructose,aspartame or saccharin; flavoring agents such as peppermint, oil ofwintergreen, or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation. Moreover, in tablet or pillform, the compositions may be coated to delay disintegration andabsorption in the gastrointestinal tract, thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compounds of the disclosure. In these laterplatforms, fluid from the environment surrounding the capsule is imbibedby the driving compound, which swells to displace the agent or agentcomposition through an aperture. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations. A time delay material suchas glycerol monostearate or glycerol stearate may also be used. Oralcompositions can include standard vehicles such as mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate, etc. Such vehicles are preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5.0 mM to about 50.0 mM) etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

For buccal administration, the pharmaceutical compositions may take theform of tablets, lozenges, etc. formulated in conventional manner.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the disclosure with a pharmaceutically acceptable vehicle. In someembodiments, the pharmaceutically acceptable vehicle is a liquid such asalcohol, water, polyethylene glycol or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of compounds disclosed herein. Preferably, thismaterial is liquid such as an alcohol, glycol, polyglycol or a fattyacid. Other methods of formulating liquid drug solutions or suspensionsuitable for use in aerosol devices are known to those of skill in theart (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat.No. 5,556,611).

The present compounds, or salts, solvates, esters, and/or prodrugsthereof, may also be formulated in rectal or vaginal pharmaceuticalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, may alsobe formulated as a depot preparation. Such long acting formulations maybe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thepresent compounds, or salts, solvates, esters, and/or prodrugs thereof,may be formulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

5.7 Therapeutic Doses

The present compounds, or a salt, prodrug or softdrug, salt of prodrugor softdrug, solvate or hydrate thereof and a pharmaceuticallyacceptable vehicle is provided, will generally be used in an amounteffective to achieve the intended purpose. For use to treat or preventdiseases or disorders characterized by down regulated apoptosis thecompounds and/or pharmaceutical compositions thereof, are administeredor applied in a therapeutically effective amount.

The amount of the present compounds, or salts, solvates, esters, and/orprodrugs thereof, that will be effective in the treatment of aparticular disorder or condition disclosed herein will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques known in the art. In addition, in vitro or in vivoassays may optionally be employed to help identify optimal dosageranges. The amount of the present compounds, or salts, solvates, esters,and/or prodrugs thereof, administered will, of course, be dependent on,among other factors, the subject being treated, the weight of thesubject, the severity of the affliction, the manner of administrationand the judgment of the prescribing physician.

For example, the dosage may be delivered in a pharmaceutical compositionby a single administration, by multiple applications or controlledrelease. In some embodiment, the present compounds, or salts, solvates,esters, and/or prodrugs thereof, are delivered by oral sustained releaseadministration. Dosing may be repeated intermittently, may be providedalone or in combination with other drugs and may continue as long asrequired for effective treatment of the disease state or disorder.

Suitable dosage ranges for oral administration (the oral unit dosageform) to a patient in need depend on the potency of the presentcompounds, but are generally between about 0.001 mg to about 200 mg of acompound of the disclosure per kilogram body weight; more preferably,between about 0.01 mg to about 50 mg of a compound of the disclosure perkilogram body weight; still more preferably, between about 0.05 mg toabout 20 mg of a compound of the disclosure per kilogram body weight;and the patient is an animal; more preferably, a mammal; and mostpreferably, a human. Dosage ranges may be readily determined by methodsknown to the artisan of ordinary skill.

Suitable dosage ranges for intravenous (i.v.) administration to apatient in need are about 0.001 mg to about 100 mg per kilogram bodyweight; more preferably, between about 0.01 mg to about 20 mg of acompound of the disclosure per kilogram body weight; and the patient isan animal; more preferably, a mammal; and most preferably, a human.Suitable dosage ranges for intranasal administration to a patient inneed are generally about 0.001 mg/kg body weight to about 10 mg/kg bodyweight; more preferably, between about 0.01 mg to about 1 mg of acompound of the disclosure per kilogram body weight; and the patient isan animal; more preferably, a mammal; and most preferably, a human.Suppositories generally contain about 0.01 milligram to about 50milligrams of a compound of the disclosure per kilogram body weight andcomprise active ingredient in the range of about 0.5% to about 10% byweight. Recommended dosages for intradermal, intramuscular,intraperitoneal, subcutaneous, epidural, sublingual or intracerebraladministration to a patient in need are in the range of about 0.001 mgto about 200 mg per kilogram of body weight; and the patient is ananimal; more preferably, a mammal; and most preferably, a human.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems. Such animal models andsystems are well-known in the art.

The present compounds, or salts, solvates, esters, and/or prodrugsthereof, are preferably assayed in vitro and in vivo, for the desiredtherapeutic or prophylactic activity, prior to use in humans. Forexample, in vitro assays can be used to determine whether administrationof a specific compound of the disclosure or a combination of compoundsis preferred for inducing apoptosis or signal transduction in cellswhich over-express bcl-2 proteins or protein kinases. The presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, may alsobe demonstrated to be effective and safe using animal model systems.

Preferably, a therapeutically effective dose of the present compounds,or salts, solvates, esters, and/or prodrugs thereof, will providetherapeutic benefit without causing substantial toxicity. Toxicity ofthe present compounds, or salts, solvates, esters, and/or prodrugsthereof, may be determined using standard pharmaceutical procedures andmay be readily ascertained by the skilled artisan. The dose ratiobetween toxic and therapeutic effect is the therapeutic index. Thepresent compounds, or salts, solvates, esters, and/or prodrugs thereof,generally exhibit particularly high therapeutic indices in treatingapoptosis associated disease and disorders. The dosage of the presentcompounds, or salts, solvates, esters, and/or prodrugs thereof, willpreferably be within a range of circulating concentrations that includean effective dose with little or no toxicity.

5.8 Combination Therapy

In certain embodiments of the present disclosure, the present compounds,or salts, solvates, esters, and/or prodrugs thereof, can be used incombination therapy with at least one additional active or therapeuticagent. The present compounds, or salts, solvates, esters, and/orprodrugs thereof, and the at least one additional active or therapeuticagent can act additively or, more preferably, synergistically. In someembodiments, the present compounds, or salts, solvates, esters, and/orprodrugs thereof are administered concurrently, sequentially, orseparately with the administration of another therapeutic agent.Exemplary active or chemotherapeutic agents include, but are not limitedto, aceglatone, aclarubicin, altretamine, aminoglutethimide;5-aminogleavulinic acid, amsacrine, anastrozole, ancitabinehydrochloride, 17-1a antibody, antilymphocyte immunoglobulins,antineoplaston a10, asparaginase, pegaspargase, azacitidine,azathioprine, batimastat, benzoporphyrin derivative, bicalutamide,bisantrene hydrochloride, bleomycin sulphate, brequinar sodium,broxuridine, busulphan, campath-ih, caracemide, carbetimer, carboplatin,carboquone, carmofur, carmustine, chlorambucil, chlorozotocin,chromomycin, cisplatin, cladribine, corynebacterium parvum,cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin,daunorubicin hydrochloride, decitabine, diaziquone,dichlorodiethylsulphide, didemnin b., docetaxel, doxifluridine,doxorubicin hychloride, droloxifene, echinomycin, edatrexate,elliptinium, elmustine, enloplatin, enocitabine, epirubicinhydrochloride, erlotinib, estramustine sodium phosphate, etanidazole,ethoglucid, etoposide, fadrozole hydrochloride, fazarabine, fenretinide,floxuridine, fludarabine phosphate, fluorouracil, flutamide, formestane,fotemustine, gallium nitrate, gemcitabine, gusperimus,homoharringtonine, hydroxyurea, idarubicin hydrochloride, ifosfamide,ilmofosine, improsulfan tosylate, inolimomab, interleukin-2; irinotecan,jm-216, letrozole, lithium gamolenate, lobaplatin, lomustine,lonidamine, mafosfamide, meiphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, miboplatin, miltefosine,misonidazole, mitobronitol, mitoguazone dihydrochioride, mitolactol,mitomycin, mitotane, mitozanetrone hydrochloride, mizoribine, mopidamol,muitlaichilpeptide, muromonab-cd3, mustine hydrochloride, mycophenolicacid, mycophenolate mofetil, nedaplatin, nilutamide, nimustinehydrochloride, oxaliplatin, paclitaxel, pcnu, penostatin, peplomycinsulphate, pipobroman, pirarubicin, piritrexim isethionate, piroxantronehydrochloride, plicamycin, porfimer sodium, prednimustine, procarbazinehydrochloride, raltitrexed, ranimustine, razoxane, rogletimide,roquinimex, sebriplatin, semustine, sirolimus, sizofiran, sobuzoxane,sodium bromebrate, sorafenib, sparfosic acid, sparfosate sodium,sreptozocin, sulofenur, tacrolimus, tamoxifen, tegafur, teloxantronehydrochloride, temozolomide, teniposide, testolactone, tetrasodiummesotetraphenylporphine-sulphonate, thioguanine, thioinosine, thiotepa,topotecan, toremifene, treosulfan, trimetrexate, trofosfamide, tumornecrosis factor, ubenimex, uramustine, vinblastine sulphate, vincristinesulphate, vindesine sulphate, vinorelbine tartrate, vorozole,zinostatin, zolimomab aritox, and zorubicin hydrochloride, and the like,either individually or in any combination, an inhibitor of proteinkinase A (PKA), an inhibitor of cAMP signaling, an inhibitor of a PKC(epsilon or alpha or beta) protein kinase, an inhibitor of Bcl-2 (Bcl-2,or MCL-1, or Bcl-xL), a nonsteroidal anti-inflammatory drug, aprostaglandin synthesis inhibitor, a local anesthetic, ananticonvulsant, an antidepressant, an opioid receptor agonist, and aneuroleptic, a benzodiazepine, a barbiturate, a neurosteroid and ainhalation anesthetic, an anesthetic and another pain killer.

The foregoing detailed description has been given for clearness ofunderstanding only and no unnecessary limitations should be understoodtherefrom as modifications will be obvious to those skilled in the art.It is not an admission that any of the information provided herein isprior art or relevant to the presently claimed disclosures, or that anypublication specifically or implicitly referenced is prior art.

Embodiments of this disclosure are described herein, including the bestmode known to the inventors for carrying out the disclosure. Variationsof those preferred embodiments may become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the disclosure to be practiced otherwise thanas specifically described herein. Accordingly, this disclosure includesall modifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the disclosure unless otherwise indicatedherein or otherwise clearly contradicted by context.

INCORPORATION BY REFERENCE

All references, articles, publications, patents, patent publications,and patent applications cited herein are incorporated by reference intheir entireties for all purposes.

However, mention of any reference, article, publication, patent, patentpublication, and patent application cited herein is not, and should notbe taken as, an acknowledgment or any form of suggestion that theyconstitute valid prior art or form part of the common general knowledgein any country in the world.

What is claimed is:
 1. A compound having a structural formula (I):

or a salt, or solvate thereof; wherein: A¹ and A² are independentlyoxygen or sulfur; R¹ is selected from the group consisting of hydrogen,—(CH₂)_(n)halogen, —CN, —CH₃, NH₂, NHR^(a), C₁₋₆ alkyl,N(CHR)_(n)C₃₋₁₀cycloalkyl, wherein said cycloalkyl can be independentlyoptionally substituted with 1 or 2 groups of C₁₋₆ alkyl, halogen, CN,NO₂, NH₂, NHR^(a), SO₂R¹¹, and NR^(a)SO₂R¹¹; R is selected fromHydrogen, halogen, CN, NO₂, NH₂, or C₁₋₆ alkyl; R² is selected from thegroup consisting of:

wherein each recited R² cycloalkyl or heterocycle can be independentlyoptionally substituted with 1 or 2 groups of C₁₋₆ alkyl, halogen, CN,NO₂, NH₂, NHR^(a), SO₂R¹¹, and R³, R⁵, R⁶, and R⁹ are independently R⁷;R⁴ is selected from the group consisting of: halogen, CN, NO₂, CF₃,—(CHR)_(n)COOR¹¹, —(CHR)_(n)SO₂R¹¹, C₁₋₄ haloalkyl, —OC₁₋₄-haloalkyl,C₂₋₆ alkyl, —(CHR)_(n)C(O)CF₃, —(CHR)_(n)C(OH)(CF₃)₂, —(CH₂)_(n)halogen,—OR¹⁰, —NR¹¹R¹², —NR^(a)COR¹¹, —NR^(a)COOR¹¹, —NR^(a)SO₂R¹¹,—NR^(a)CONR¹¹R¹², —COR¹¹, tetrazole, —(CHR)_(n)tetrazole, —S—C₁₋₆ alkyl,or —CONR¹¹R¹², —C(O)OR¹¹, —SO₂NHC(═O)CH₃, —C(CF₃)(CF₃)OH, —SO₂NH₂,—C(O)CF₃,

R⁷ and R¹⁰ are independently selected from the group consisting of:hydrogen, halogen, CN, NH₂, NO₂, C₁₋₄ haloalkyl, —OC₁₋₄ haloalkyl, C₁₋₆alkyl, —C(O)CF₃, —(CH₂)_(n)halogen, —OR^(a), and NR^(a)R^(a); R¹¹ andR¹² are independently selected from the group consisting of: hydrogen,NR^(a)C(═O)R, halogen, CN, NH₂, NHR^(a), NO₂, C₁₋₄ haloalkyl, —OC₁₋₄haloalkyl, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —C(═O)—(O)_(n)—R^(a), and —OR^(a),wherein one or more carbon atoms of said alkyl may be replaced with oneor more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur; R^(a) each independently represents hydrogen or C₁₋₆alkyl; and n represents an integer from 0 to
 3. 2. The compoundaccording to claim 1, which is selected from the group consisting of:4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]aminoanthracene-9,10-dione; methyl4-[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;2-(dimethylamino)ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;2-(dimethylamino)ethyl4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;and1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione,or a salt, or solvate thereof.
 3. The compound according to claim 1,which is:


4. A compound having a structural formula (II):

or a salt, or solvate thereof; wherein: X represents N or CH; R⁴ isselected from the group consisting of: —C(O)OR¹¹, —C(CF₃)(CF₃)OH, —CF₃,—(CHR)_(n)COOR¹¹, —(CHR)_(n)SO₂R¹¹, —(CHR)_(n)C(OH)(CF₃)₂,

R¹¹ is selected from the group consisting of: hydrogen, NR^(a)C(═O)R,halogen, CN, NH₂, NHR^(a), NO₂, C₁₋₄ haloalkyl, —OC₁₋₄ haloalkyl,—S—C₁₋₆ alkyl, —C(═O)—(O)_(n)—R^(a), —OR^(a), or C₁₋₆ alkyl, wherein oneor more carbon atoms of said alkyl may be replaced with one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur; R represents hydrogen, halogen, CN, NO₂, or C₁₋₆ alkyl; R^(a)each independently represents hydrogen or C₁₋₆ alkyl; and n represents0.
 5. The compound according to claim 4, which is selected from thegroup consisting of:4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;methyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;2-(dimethylamino)ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;and ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;or a salt, or solvate thereof.
 6. A pharmaceutical composition,comprising: a) a therapeutically effective amount of a compoundaccording to claim 1, or a salt, or solvate thereof; and b) apharmaceutically acceptable vehicle or carrier.
 7. The pharmaceuticalcomposition according to claim 6, wherein the compound is selected fromthe group consisting of:4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;methyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;2-(dimethylamino)ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;2-(dimethylamino)ethyl4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;and1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione,or a salt, or solvate thereof.
 8. The pharmaceutical compositionaccording to claim 6, wherein the compound is:


9. The pharmaceutical composition according to claim 6, wherein saidpharmaceutical composition is formulated in a unit dosage form selectedfrom the group consisting of: an oral unit dosage form, an injectionunit dosage form, a transdermal patch unit dosage form, or animplantation of a depot formulation unit dosage form.
 10. Apharmaceutical composition, comprising: a) a therapeutically effectiveamount of a compound according to claim 4, or a salt, or solvatethereof; and b) a pharmaceutically acceptable vehicle or carrier. 11.The pharmaceutical composition according to claim 10, wherein thecompound is selected from the group consisting of:4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;methyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;2-(dimethylamino)ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;and ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;or a salt, or solvate thereof.
 12. The pharmaceutical compositionaccording to claim 10, wherein said pharmaceutical composition isformulated in a unit dosage form selected from the group consisting of:an oral unit dosage form, an injection unit dosage form, a transdermalpatch unit dosage form, or an implantation of a depot formulation unitdosage form.
 13. The pharmaceutical composition according to claim 12,wherein the compound is:


14. A method for ameliorating pain in a patient suffering therefrom,comprising: a) administering to the patient a therapeutically effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, and wherein the pain is selectedfrom the group consisting of: acute pain, chronic pain, inflammatorypain, neuropathic pain, tonic pain, persistent pain, postoperative pain,osteoarthritis pain, diabetic neuropathic pain, chemical-induced pain,chemotherapy-induced pain, cancer-pain, drug-induced pain, bone pain,pain associated with alcohol-induced hyperalgesia, a generalized paindisorder, and combinations thereof.
 15. A method for ameliorating acuteor chronic pain in a patient suffering therefrom, comprising: a)administering to the patient a therapeutically effective amount of acompound according to claim 4, or a pharmaceutically acceptable salt, orsolvate thereof.
 16. The method according to claim 14, wherein thecompound administered is selected from the group consisting of:4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;methyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;2-(dimethylamino)ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;2-(dimethylamino)ethyl4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;and1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione,or a salt, or solvate thereof.
 17. The method according to claim 14,wherein the compound administered is:


18. The method according to claim 15, wherein the compound administeredis selected from the group consisting of:4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoicacid;N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;methyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;2-(dimethylamino)ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;and ethyl4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;or a salt, or solvate thereof.
 19. The method according to claim 15,wherein the compound administered is:


20. A synergistic method for reducing tumor growth of a pancreaticcancer in a patient suffering therefrom, comprising: a) administering tothe patient a therapeutically effective amount of gemcitabine; and b)administering to the patient a therapeutically effective amount acompound having the following structure:

or a pharmaceutically acceptable salt, or solvate thereof, wherein thecombination of gemcitabine and the aforementioned compound exhibit asynergistic effect on tumor reduction.